N-carboxymethyl substituted benzolactams as inhibitors of matrix metalloproteinase

ABSTRACT

The present invention provides a method of inhibiting matrix metallo-proteinases (MMPs) in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of the N-carboxymethyl substituted benzolactams of formula (1):                    
     wherein A is —OH or —NRR′. Such inhibitors are useful in treating neoplasms, atherosclorosis, and chronic inflammatory diseases. 
     The present invention also provides novel N-carboxymethyl substituted benzolactams of formula (1a):                    
     wherein A is —NRR′.

This is a continuation application of U.S. application Ser. No.09/465,737 filed on Dec. 17, 1999.

This application claims the benefit of U.S. Provisional Application No.60/172,244 filed Dec. 31, 1998.

BACKGROUND OF THE INVENTION

The matrix metalloproteinases (MMPs) are a family of zinc containingendopeptidases which are capable of cleaving large biomolecules such asthe collagens, proteoglycans and gelatins. Expression is upregulated bypro-inflammatory cytokines and/or growth factors. The MMP's are secretedas inactive zymogens which, upon activation, are subject to control byendogenous inhibitors, for example, tissue inhibitor ofmetalloproteinases (TIMP) and α₂-macroglobulin. Chapman, K. T. et al.,J. Med. Chem. 36, 4293-4301 (1993); Beckett, R. P. et al., DDT 1, 16-26(1996). The characterizing feature of diseases involving the enzymesappears to be a stoichiometric imbalance between active enzymes andendogenous inhibitors, leading to excessive tissue disruption, and oftendegradation. McCachren, S. S., Arthritis Rheum. 34, 1085-1093 (1993).

The discovery of different families of matrix metalloproteinase, theirrelationships, and their individual characteristics have beencategorized in several reports. Emonard, H. et al., Cell Molec. Biol.36, 131-153 (1990); Birkedal-Hansen, H., J. Oral Pathol. 17,445-451(1988); Matrisian, L. M., Trends Genet. 6, 121-125 (1990); Murphy, G. J.P. et al., FEBS Lett. 289, 4-7 (1991); Matrisian, L. M., Bioessays 14,455-463 (1992). Three groups of MMPs have been delineated: thecollagenases which have triple helical interstitial collagen as asubstrate, the gelatinases which are proteinases of denatured collagenand Type IV collagen, and the stromelysins which were originallycharacterized as proteoglycanases but have now been identified to have abroader characterized as proteoglycanases but have now been identifiedto have a broader proteolytic spectrum. Examples of specificcollagenases include fibroblast collagenase (MMP-1), neutrophilcollagenase (MMP-8), and collagenase 3 (MMP-13). Examples of gelatinasesinclude 72 kDa gelatinase (gelatinase A; MMP-2) and 92 kDa gelatinase(gelatinase B; MMP-9). Examples of stromelysins include stromelysin 1(MMP-3), stromelysin 2 (MMP-10) and matrilysin (MMP-7). Other MMPs whichdo not fit neatly into the above groups include metalloelastase(MMP-12), membrane-type MMP (MT-MMP or MMP-14) and stromelysin 3(MMP-11). Beckett, R. P. et al., supra.

Over-expression and activation of MMPs have been linked with a widerange of diseases such as cancer; rheumatoid arthritis; osteoarthritis;chronic inflammatory disorders, such as emphysema and smoking-inducedemphysema; cardiovascular disorders, such as atherosclerosis; cornealulceration; dental diseases such as gingivitis and periodontal disease;and neurological disorders, such as multiple sclerosis. For example, inadenocarcinoma, invasive proximal gastric cells express the 72 kDa formof collagenase Type IV, whereas the noninvasive cells do not. Schwartz,G. K. et al., Cancer 73, 22-27 (1994). Rat embryo cells transformed bythe Ha-ras and v-myc oncogenes or by Ha-ras alone are metastatic in nudemice and release the 92 kDa gelatinase/collagenase (MMP-9). Bernhard, E.J. et al., Proc. Natl. Acad. Sci. 91, 4293-4597 (1994). The plasmaconcentration of MMP-9 was significantly increased (P<0.01) in 122patients with gastrointestinal tract cancer and breast cancer. Zucker,S. et al., Cancer Res. 53, 140-146 (1993). Moreover, intraperitonealadministration of batimastat, a synthetic MMP inhibitor, gavesignificant inhibition in the growth and metastatic spread and number oflung colonies which were produced by intravenous injection of theB16-BL6 murine melanoma in C57BL/6N mice. Chirivi, R. G. S. et al., Int.J. Cancer 58, 460-464 (1994). Over-expression of TIMP-2, the endogenoustissue inhibitor of MMP-2, markedly reduced melanoma growth in the skinof immunodeficient mice. Montgomery, A. M. P. et al., Cancer Res. 54,5467-5473 (1994).

Accelerated breakdown of the extracellular matrix of articular cartilageis a key feature in the pathology of both rheumatoid arthritis andosteoarthritis. Current evidence suggests that the inappropriatesynthesis of MMPs is the key event. Beeley, N. R. A. et al., Curr. Opin.Ther. Patents, 4(1), 7-16 (1994). The advent of reliable diagnostictools have allowed a number of research groups to recognize thatstromelysin is a key enzyme in both arthritis and joint trauma Beeley,N. R. A. et al., Id.; Hasty, K. A. et al., Arthr. Rheum. 33, 388-397(1990). It has also been shown that stromelysin is important for theconversion of procollagenase to active collagenase. Murphy, G. et al.,Biochem. J. 248, 265-268 (1987).

Furthermore, a range of MMPs can hydrolyse the membrane-bound precursorof the pro-inflammatory cytokine tumor necrosis factor α (TNF-α).Gearing, A. J. H. et al., Nature 370, 555-557 (1994). This cleavageyields mature soluble TNF-α and the inhibitors of MMPs can blockproduction of TNF-α both in vitro and in vivo. Gearing, A. J. H. et al.,Id.; Mohler, K. M. et al., Nature 370, 218-220 (1994); McGeehan, G. M.et al., Nature 370, 558-561 (1994). This pharmacological action is aprobable contributor to the antiarthritic action of this class ofcompounds seen in animal models. Beckett, R. P. et al., supra.

Stromelysin has been observed to degrade the α₁-proteinase inhibitorwhich regulates the activity of enzymes such as elastase, excesses ofwhich have been linked to chronic inflammatory disorders such asemphysema and chronic bronchitis. Beeley, N. R. A. et al., supra.; Wahl,R. C. et al., Annual Reports in Medicinal Chemistry 25, 177-184 (1990).In addition, a recent study indicates that MMP-12 is required for thedevelopment of smoking-induced emphysema in mice. Science, 277, 2002(1997). Inhibition of the appropriate MMP may thus potentiate theinhibitory activity of endogenous inhibitors of this type.

High levels of mRNA corresponding to stromelysin have been observed inatherosclerotic plaques removed from heart transplant patients. Henney,A. M., et al., Proc. Natl. Acad. Sci. 88, 8154-8158 (1991). It issubmitted that the role of stromelysin in such plaques is to encouragerupture of the connective tissue matrix which encloses the plaque. Thisrupture is in turn thought to be a key event in the cascade which leadsto clot formation of the type seen in coronary thrombosis. MMPinhibition is thus a preventive measure for such thromboses.

Collagenase, stromelysin and gelatinase have been implicated in thedestruction of the extracellular matrix of the cornea. This is thoughtto be an important mechanism of morbidity and visual loss in a number ofulcerative ocular diseases, particularly those following infection orchemical damage. Burns, F. R. et al., Invest. Opthalmol. and Visual Sci.32, 1569-1575 (1989). The MMPs present in the eye during ulceration arederived either endogenously from infiltrating leucocytes or fibroblasts,or exogenously from microbes.

Collagenase and stromelysin activities have been identified infibroblasts isolated from inflamed gingiva and the levels of enzyme havebeen correlated with the severity of the gingivitis observed. Beeley, N.R. A. et al., supra; Overall, C. M. et al., J. Periodontal Res. 22,81-88 (1987).

Excessive levels of gelatinase-B in cerebrospinal fluid has been linkedwith incidence of multiple sclerosis and other neurological disorders.Beeley, N. R. A. et al., supra.; Miyazaki, K. et al., Nature 362,839-841 (1993). The enzyme may play a key role in the demyelination ofneurones and the breakdown of the blood brain barrier which occurs insuch disorders.

SUMMARY OF THE INVENTION

The present invention provides a method of inhibiting matrixmetallo-proteinases (MMPs) in a patient in need thereof comprisingadministering to the patient an effective matrix metalloproteinaseinhibiting amount of the N-carboxymethyl substituted benzolactams offormula (1):

wherein

A is selected from the group consisting of —OH and —NRR′;

wherein

R and R′ are independently selected from the group consisting ofhydrogen and C₁-C₆ alkyl or R and R′ taken together with the nitrogenatom to which they are attached form a N-morpholino, N-piperidino,N-pyrrolidino, or N-isoindolyl;

R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl,—(CH₂)_(a)—CO₂R₅, —(CH₂)_(a)—C(O)NH₂, —(CH₂)₄NH₂, —(CH₂)₃—NH—C(NH)NH₂,—(CH₂)₂—S(O)_(b)—CH₃, —CH₂—OH,

—CH(OH)CH₃, —CH₂—SH, —(CH₂)_(d)—Ar₁, and —CH₂—Ar₂;

wherein

a is 1 or 2;

b is 0, 1, or 2;

d is an integer from 0 to 4;

R₅ is selected from the group consisting of hydrogen, C₁-C₄ alkyl, andbenzyl;

Ar₁ is a radical selected from the group consisting of

wherein

R₆ is from 1 to 2 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄ alkoxy;

R₇ is selected from the group consisting of hydrogen, halogen, C₁-C₄alkyl, and C₁-C₄ alkoxy;

Ar₂ is a radical selected from the group consisting of

R₂ is from 1 to 2 substituents independently selected from the groupconsisting of hydrogen, halogen, hydroxy C₁-C₄ alkyl, and C₁-C₄ alkoxy;

R₃ is selected from the group consisting of C₁-C₆ alkyl, —(CH₂)_(m)—W,—(CH₂)_(p)—Ar₃, —(CH₂)_(k)—CO₂R₉, —(CH₂)_(m)—NR_(8′)SO₂—Y₁, and—(CH₂)_(m)-Z-Q

wherein

m is an integer from 2 to 8;

p is an integer from 0-10;

k is an integer from 1 to 9;

W is phthalimido;

Ar₃ is selected from the group consisting of

wherein

R₂₃ is from 1 to 2 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy;

R_(8′) is hydrogen or C₁-C₆ alkyl;

R₉ is hydrogen or C₁-C₆ alkyl;

Y₁ is selected from the group consisting of hydrogen, —(CH₂)_(j)—Ar₄,and —N(R₂₄)₂

wherein

j is 0 or 1;

R₂₄ each time selected is independently hydrogen or C₁-C₆ alkyl or aretaken together with the nitrogen to which they are attached to formN-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;

Ar₄ is

wherein

R₂₅ is from 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy;

Z is selected from the group consisting of —O—, —NR₈—, —C(O)NR₈—,—NR₈C(O)—, —NR₈C(O)NH—, —NR₈C(O)O—, and —OC(O)NH—;

wherein

R₈ is hydrogen or C₁-C₆ alkyl;

Q is selected from the group consisting of hydrogen, —(CH₂)_(n)—Y₂, and—(CH₂)_(x)Y₃;

wherein

n is an integer from 0 to 4;

Y₂ is selected from the group consisting of hydrogen, —(CH₂)_(h)—Ar₅ and—(CH₂)_(t)—C(O)OR₂₇

wherein

Ar₅ is selected from the group consisting of

wherein

R₂₆ is from 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy;

h is an integer from 0 to 6;

t is an integer from 1 to 6;

R₂₇ is hydrogen or C₁-C₆ alkyl;

x is an integer from 2 to 4;

Y₃ is selected from the group consisting of —N(R₂₈)₂, N-morpholino,N-piperidino, N-pyrrolidino, and N-isoindolyl;

wherein

R₂₈ each time taken is independently selected from the group consistingof hydrogen and C₁-C₆ alkyl;

R₄ is selected from the group consisting of hydrogen, —C(O)R₁₀,—C(O)—(CH₂)_(q)—K and —S-G

wherein

R₁₀ is selected from the group consisting of hydrogen, C₁-C₄ alkyl,phenyl, and benzyl;

q is 0, 1, or 2;

K is selected from the group consisting of

wherein

V is selected from the group consisting of a bond, —CH₂—, —O—,—S(O)_(r)—, —NR₂₁—, and —NC(O)R₂₂;

wherein

r is 0, 1, or 2;

R₂₁ is selected from the group consisting of hydrogen, C₁-C₄ alkyl, andbenzyl;

R₂₂ is selected from the group consisting of hydrogen, —CF₃, C₁-C₁₀alkyl, phenyl, and benzyl;

R₁₁ each time taken is independently selected from the group consistingof hydrogen, C₁-C₄ alkyl, and benzyl;

G is selected from the group consisting of

wherein

w is an integer from 1 to 3;

R₁₂ is selected from the group consisting of hydrogen, C₁-C₆ alkyl,—CH₂CH₂S(O)_(u)CH₃, and benzyl;

wherein

u is 0, 1, or 2;

R₁₃ is selected from the group consisting of hydrogen, hydroxy, amino,C₁-C₆ alkyl, N-methylamino, N,N-dimethylamino, —CO₂R₁₇, and —OC(O)R₁₈;

wherein

R₁₇ is hydrogen, —CH₂O—C(O)C(CH₃)₃, C₁-C₄ alkyl, benzyl, ordiphenylmethyl;

R₁₈ is hydrogen, C₁-C₆ alkyl or phenyl;

R₁₄ is 1 or 2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen;

V₁ is selected from the group consisting of —O—, —S—, and —NH—;

V₂ is selected from the group consisting of —N— and —CH—,

V₃ is selected from the group consisting of a bond and —C(O)—;

V₄ is selected from the group consisting of —O—, —S—, —NR₁₉—, and—NC(O)R₂₀—;

wherein

R₁₉ is hydrogen, C₁-C₄ alkyl, or benzyl;

R₂₀ is hydrogen, —CF₃, C₁-C₁₀ alkyl, or benzyl;

R₁₅ is selected from the group consisting of hydrogen, C₁-C₆ alkyl andbenzyl;

R₁₆ is selected from the group consisting of hydrogen and C₁-C₄ alkyl;and stereoisomers, pharmaceutically acceptable salt, and hydratethereof.

Novel N-carboxymethyl substituted benzolactams are encompassed byformula (1). Some of these novel compounds are described by of formula(1a), below, which is encompassed by formula (1). The present inventionprovides novel N-carboxymethyl substituted benzolactams of formula (1a):

wherein

Aa is —NRR′;

wherein

R and R′ are independently selected from the group consisting ofhydrogen and C₁-C₆ alkyl or R and R′ taken together with the nitrogenatom to which they are attached form a N-morpholino, N-piperidino,N-pyrrolidino, or N-isoindolyl;

R₁ is selected from the group consisting of hydrogen, C₁-C₆ alkyl,(CH₂)_(a)—CO₂R₅, —(CH₂)_(a)—C(O)NH₂, —(CH₂)₄NH₂, —(CH₂)₃—NH—C(NH)₂,—(CH₂)₂—S(O)_(b)—CH₃, —CH₂—OH,

—CH(OH)CH₃, —CH₂—SH, —(CH₂)_(d)—Ar₁, and —CH₂—Ar₂;

wherein

a is 1 or 2;

b is 0, 1, or 2;

d is an integer from 0 to 4;

R₅ is selected from the group consisting of hydrogen, C₁-C₄ alkyl, andbenzyl;

Ar₁ is a radical selected from the group consisting of

wherein

R₆ is from 1 to 2 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄ alkoxy;

R₇ is selected from the group consisting of hydrogen, halogen, C₁-C₄alkyl, and C₁-C₄ alkoxy;

Ar₂ is a radical selected from the group consisting of

R₂ is from 1 to 2 substituents independently selected from the groupconsisting of hydrogen, halogen, hydroxy C₁-C₄ alkyl, and C₁-C₄ alkoxy;

R₃ is selected from the group consisting of C₁-C₆ alkyl, —(CH₂)_(m)—W,—(CH₂)_(p)—Ar₃, —(CH₂)_(k)—CO₂R₉, —(CH₂)_(m)—NR_(8′)SO₂—Y₁, and—(CH₂)_(m)-Z-Q

wherein

m is an integer from 2 to 8;

p is an integer from 0-10;

k is an integer from 1 to 9;

W is phthalimido;

Ar₃ is selected from the group consisting of

wherein

R₂₃ is from 1 to 2 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy;

R_(8′) is hydrogen or C₁-C₆ alkyl;

R₉ is hydrogen or C₁-C₆ alkyl;

Y₁ is selected from the group consisting of hydrogen, —(CH₂)_(j)—Ar₄,and —N(R₂₄)₂

wherein

j is 0 or 1;

R₂₄ each time selected is independently hydrogen or C₁-C₆ alkyl or aretaken together with the nitrogen to which they are attached to formN-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl;

Ar₄ is

wherein

R₂₅ is from 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy;

Z is selected from the group consisting of —O—, —NR₈—, —C(O)NR₈—,—NR₈C(O)—, —NR₈C(O)NH—, —NR₈C(O)O—, and —OC(O)NH—;

wherein

R₈ is hydrogen or C₁-C₆ alkyl;

Q is selected from the group consisting of hydrogen, —(CH₂)_(n)—Y₂, and—(CH₂)_(x)Y₃;

wherein

n is an integer from 0 to 4;

Y₂ is selected from the group consisting of hydrogen, —(CH₂)_(h)—Ar₅ and—(CH₂)_(t)—C(O)OR₂₇

wherein

Ar₅ is selected from the group consisting of

wherein

R₂₆ is from 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy;

h is an integer from 0 to 6;

t is an integer from 1 to 6;

R₂₇ is hydrogen or C₁-C₆ alkyl;

x is an integer from 2 to 4;

Y₃ is selected from the group consisting of —N(R₂₈)₂, N-morpholino,N-piperidino, N-pyrrolidino, and N-isoindolyl;

wherein

R₂₈ each time taken is independently selected from the group consistingof hydrogen and C₁-C₆ alkyl;

R₄ is selected from the group consisting of hydrogen, —C(O)R₁₀,—C(O)—(CH₂)_(q)—K and —S-G

wherein

R₁₀ is selected from the group consisting of hydrogen, C₁-C₄ alkyl,phenyl, and benzyl;

q is 0, 1, or 2;

K is selected from the group consisting of

wherein

V is selected from the group consisting of a bond, —CH₂—, —O—,—S(O)_(r)—, —NR₂₁—, and —NC(O)R₂₂;

wherein

r is 0, 1, or 2;

R₂₁ is selected from the group consisting of hydrogen, C₁-C₄ alkyl, andbenzyl;

R₂₂ is selected from the group consisting of hydrogen, —CF₃, C₁-C₁₀alkyl, phenyl, and benzyl;

R₁₁ each time taken is independently selected from the group consistingof hydrogen, C₁-C₄ alkyl, and benzyl;

G is selected from the group consisting of

wherein

w is an integer from 1 to 3;

R₁₂ is selected from the group consisting of hydrogen, C₁-C₆ alkyl,—CH₂CH₂S(O)_(u)CH₃, and benzyl;

wherein

u is 0, 1, or 2;

R₁₃ is selected from the group consisting of hydrogen, hydroxy, amino,C₁-C₆ alkyl, N-methylamino, N,N-dimethylamino, —CO₂R₁₇, and —OC(O)R₁₈;

wherein

R₁₇ is hydrogen, —CH₂O—C(O)C(CH₃)₃, C₁-C₄ alkyl, benzyl, ordiphenylmethyl;

R₁₈ is hydrogen, C₁-C₆ alkyl or phenyl;

R₁₄ is 1 or 2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen;

V₁ is selected from the group consisting of —O—, —S—, and —NH—;

V₂ is selected from the group consisting of —N— and —CH—;

V₃ is selected from the group consisting of a bond and —C(O)—;

V₄ is selected from the group consisting of —O—, —S—, —NR₁₉—, and—NC(O)R₂₀—;

wherein

R₁₉ is hydrogen, C₁-C₄ alkyl, or benzyl;

R₂₀ is hydrogen, —CF₃, C₁-C₁₀ alkyl, or benzyl;

R₁₅ is selected from the group consisting of hydrogen, C₁-C₆ alkyl andbenzyl;

R₁₆ is selected from the group consisting of hydrogen and C₁-C₄ alkyl;and stereoisomers, pharmaceutically acceptable salt, and hydratethereof.

In addition, the present invention provides a composition comprising anassayable amount of a compound of formula (1a) in admixture or otherwisein association with an inert carrier. The present invention alsoprovides a pharmaceutical composition comprising an effective matrixmetallo-proteinases inhibitory amount of a compound of formula (1a) inadmixture or otherwise in association with one or more pharmaceuticallyacceptable carriers or excipients.

As is appreciated by one of ordinary skill in the art the compounds offormula (1) exist as stereoisomers. Specifically, it is recognized thatthey exist as stereoisomers at the point of attachment of thesubstituents R₁, R₃, and —SR₄, R₁₂, and —NHR₁₅ and at the point ofattachment of the group —NHC(O)CH(R₃)(SR₄) to the benzolactam. Whereindicated the compounds, whether of formula (1), starting materials, orintermediates, follow either the (+)- and (−)-designation for opticalrotation, the (D)- and (L)-designation of relative stereochemistry, orthe Cahn-Ingold-Prelog designation of (R)- and (S)- for thestereochemistry of at specific positions in the compounds represented byformula (1) and intermediates thereof. Any reference in this applicationto one of the compounds of the formula (1) is meant to encompass eitherspecific stereoisomers or a mixture of stereoisomers.

The specific stereoisomers can be prepared by stereospecific synthesisusing enantiomerically pure or enantiomerically enriched startingmaterials which are well known in the art. The specific stereoisomers ofamino acid starting materials are commercially available or can beprepared by stereospecific synthesis as is well known in the art oranalogously known in the art, such as D. A. Evans, et al. J. Am. Chem.Soc., 112, 4011-4030 (1990); S. Ikegami et al. Tetrahedron, 44,5333-5342 (1988); W. Oppolzer et al. Tet. Lets. 30, 6009-6010 (1989);Synthesis of Optically Active α-Amino-Acids, R. M. Williams (PergamonPress, Oxford 1989); M. J. O'Donnell ed.: α-Amino-Acid Synthesis,Tetrahedron Symposia in print, No. 33, Tetrahedron 44, No. 17 (1988); U.Schöllkopf, Pure Appl. Chem. 55, 1799 (1983); U. Hengartner et al. J.Org. Chem., 44, 3748-3752 (1979); M. J. O'Donnell et al. Tet. Lets.,2641-2644 (1978); M. J. O'Donnell et al. Tet. Lets. 23, 4255-4258(1982); M. J. O'Donnell et al. J. Am. Chem. Soc., 110, 8520-8525(1988).

The specific stereoisomers of either starting materials or products canbe resolved and recovered by techniques known in the art, such aschromatography on chiral stationary phases, enzymatic resolution, orfractional recrystallization of addition salts formed by reagents usedfor that purpose. Useful methods of resolving and recovering specificstereoisomers are known in the art and described in Stereochemistry ofOrganic Compounds, E. L. Eliel and S. H. Wilen, Wiley (1994) andEnantiomers, Racemates, and Resolutions, J. Jacques, A. Collet, and S.H. Wilen, Wiley (1981).

As used in this application:

a) the term “halogen” refers to a fluorine atom, chlorine atom, bromineatom, or iodine atom;

b) the term “C₁-C₆ alkyl” refers to a branched or straight chained alkylradical containing from 1 to 6 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, etc.;

c) the term “C₁-C₄ alkyl” refers to a saturated straight or branchedchain alkyl group containing from 1-4 carbon atoms and includes methyl,ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, and t-butyl;

d) the term “C₁-C₁₀ alkyl” refers to a branched or straight chainedalkyl radical containing from 1 to 6 carbon atoms, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl,heptyl, octyl, nonyl, decyl, etc.;

e) the term “C₁-C₄ alkoxy” refers to a straight or branched alkoxy groupcontaining from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, t-butoxy, etc.;

f) the designation “” refers to a bond for which the stereochemistry isnot designated;

g) the designation “” refers to a bond that protrudes forward out of theplane of the page.

h) the designation “” refers to a bond that protrudes backward out ofthe plane of the page.

i) as used in the examples and preparations, the following terms havethe meanings indicated: “g” refers to grams, “mg” refers to milligrams,“μg” refers to micrograms, “mol” refers to moles, “mmol” refers tomillimoles, “nmole” refers to nanomoles, “L” refers to liters, “mL” or“ml” refers to milliliters, “μL” refers to microliters, “° C.” refers todegrees Celsius, “R_(f)” refers to retention factor, “mp” refers tomelting point, “dec” refers to decomposition, “bp” refers to boilingpoint, “mm of Hg” refers to pressure in millimeters of mercury, “cm”refers to centimeters, “mm” refers to nanometers, “brine” refers to asaturated aqueous sodium chloride solution, “M” refers to molar, “mM”refers to millimolar, “μM” refers to micromolar, “nM” refers tonanomolar, “HPLC” refers to high performance liquid chromatography,“HRMS” refers to high resolution mass spectrum, “DMF” refers todimethylformamide, “μCi” refers to microcuries, “i.p.” refers tointraperitoneally, “i.v.” refers to intravenously, and “DPM” refers todisintegrations per minute;

j) for substituent Z, the designations —C(O)NR₈—, —NR₈C(O)—,—NR₈C(O)NH—, —NR₈C(O)O—, and —OC(O)NH— refer to the functionalitiesrepresented, respectively, by the following formulae showing theattachment of the group (Q):

these designations are referred to hereinafter as amido, amide, urea,N-carbamoyl, and O-carbamoyl, respectively;

k) the term “pharmaceutically acceptable salts thereof refers to eitheran acid addition salt or a basic addition salt.

The expression “pharmaceutically acceptable acid addition salts” isintended to apply to any non-toxic organic or inorganic acid additionsalt of the base compounds represented by formula (1) or any of itsintermediates. Illustrative inorganic acids which form suitable saltsinclude hydrochloric, hydrobromic, sulphuric, and phosphoric acid andacid metal salts such as sodium monohydrogen orthophosphate, andpotassium hydrogen sulfate. Illustrative organic acids which formsuitable salts include the mono-, di-, and tricarboxylic acids.Illustrative of such acids are for example, acetic, glycolic, lactic,pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic,cinnamic, salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid, andsulfonic acids such as methane sulfonic acid and 2-hydroxyethanesulfonic acid. Such salts can exist in either a hydrated orsubstantially anhydrous form. In general, the acid addition salts ofthese compounds are soluble in water and various hydrophilic organicsolvents, and which in comparison to their free base forms, generallydemonstrate higher melting points.

The expression “pharmaceutically acceptable basic addition salts” isintended to apply to any non-toxic organic or inorganic basic additionsalts of the compounds represented by formula (1) or any of itsintermediates. Illustrative bases which form suitable salts includealkali metal or alkaline-earth metal hydroxides such as sodium,potassium, calcium, magnesium, or barium hydroxides; ammonia, andaliphatic, alicyclic, or aromatic organic amines such as methylamine,dimethylamine, trimethylamine, and picoline.

As with any group of structurally related compounds which possess aparticular utility, certain groups and configurations of substituentsare preferred for the compounds of formula (1). Preferred embodimentsare given below:

The compounds in which R₁ is selected from the group consisting of C₁-C₆alkyl and —(CH₂)_(d)Ar₁ are preferred;

The compounds in which R₁ is —(CH₂)_(d)Ar₁ and Ar₁ is phenyl orsubstituted phenyl are more preferred;

Compounds in which R₄ is selected from the group consisting of hydrogen,—C(O)R₁₀ and —S-G are preferred;

Compounds in which R₄ is hydrogen, are more preferred;

Compounds in which R₄ is —C(O)R₁₀ and R₁₀ is C₁-C₄ alkyl more preferred;

Compounds in which A is —OH are preferred; and

Compounds in which A is —NRR′ wherein R is hydrogen and R′ is methyl arepreferred.

Examples of compounds encompassed by formula (1) and (1a) of the presentinvention include the following. It is understood that the examplesencompass all of the isomers of the compound and mixtures thereof. Thislist is meant to be representative only and is not intended to limit thescope of the invention in any way:2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, (S)—N-1-(2-methylpropyl)-2-(thio)-ethylamine, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, (R)-1-(2-methylpropyl)-2-(thio)-ethylamine, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4methyl-valeric acid, L-cysteine ethyl ester, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, N-acetyl-L-cysteine ethyl ester, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, L-cysteine, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, benzylthio, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid ethylthio, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, disulfide, 2-hydroxyethylthio, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, t-butyl ester, 2-pyridylmethylthio, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, 2-thioacetic acid morpholine carboxamide, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, t-butyl ester, benzylthio, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid t-butyl ester, ethylthio, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, t-butyl ester, disulfide, 2-hydroxyethylthio, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, t-butyl ester, 2-pyridylmethylthio, disulfide;2-(4-(2-Thio-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, t-butyl ester, 2-thioacetic acid morpholine carboxamide,disulfide.

As used herein the term “amino acid” refers to naturally occurring aminoacids as well as non-naturally occurring amino acids having substituentsencompassed by R₁ and R₂ as described above. The naturally occurringamino acids included are glycine, alanine, valine, leucine, isoleucine,serine, methionine, threonine, phenylalanine, tyrosine, tryptophan,cysteine, histidine, aspartic acid, asparagine, glutamic acid,glutamine, arginine, ornithine, and lysine. Non-naturally occurringamino acids within the term “amino acid,” include without limitation,the D-isomers of the naturally occurring amino acids, norleucine,norvaline, alloisoleucine, t-butylglycine, methionine sulfoxide, andmethionine sulfone. Other non-naturally occurring amino acids within theterm “amino acid,” include without limitation phenylalanines,phenylglycines, homophenylalanines, 3-phenylpropylglycines,4-phenylbutylglycines; each including those substituted by R₆ and R₆ asdescribed above; and 1-naphthylalanines and 2-naphthylalanines;including those substituted by R₇ and R_(7′) as described above.

The compounds of formula (1) can be prepared by utilizing techniques andprocedures well known and appreciated by one of ordinary skill in theart. To illustrate, general synthetic schemes for preparing startingmaterial, intermediates, and the compounds of formula (1) are set forthbelow. In the reaction schemes below, the reagents and startingmaterials are readily available to one of ordinary skill in the art andall substituents are as previously defined unless otherwise-indicated.

In Reaction Scheme A, step 1, a compound of formula (3) is coupled witha with an appropriate acid derivative of formula (2) to give a compoundof formula (4). Such coupling reactions are well known in the art.

An appropriate compound of structure (3) in one in which R₂ is asdesired in the final compound of formula (1), R₁ as desired in the finalproduct of formula (1) or gives rise after deprotection to R₁ as desiredin the final product of formula (1), and A′ is A or gives rise to A upondeprotection and modification, if desired, to A as desired in the finalcompound of formula (1). Appropriate compounds of formula (3) can beprepared by methods described herein and by methods well known andappreciated in the art as described in PCT International PublicationNumber WO 95/21854, published Aug. 17, 1995 and European PatentApplication Publication Number 0 599 444 A1, published Jun. 1, 1994.

An appropriate compound of formula (2) is one in which R_(3′) is R₃ asdesired in the final product of formula (1) or gives rise afterdeprotection to R₃ as desired in the final product of formula (1) and Yis a protected thio substituent or Y may be a protected hydroxysubstituent or bromo which gives rise upon selective deprotection anddisplacement or displacement and further deprotection and/orelaboration, if required, to —SR₄ as desired in the final product offormula (1). Alternately, an appropriate compound of formula (2) mayalso be one in which R_(3′) gives rise to R_(3″) which, upon fartherreaction, gives rise R₃ as desired in the final product of formula (1),as described in Reaction Scheme B, and Y is a protected thiosubstituent. In addition, an appropriate compound of formula (2) mayalso be one in which the stereochemistry at the R_(3′) and Y bearingcarbon is as desired in the final product of formula (1) or gives riseafter displacement to the stereochemistry as desired at that carbon inthe final product of formula (1).

The use and selection of appropriate protecting groups is within theability of those skilled in the art and will depend upon compound offormula (2) to be protected, the presence of other protected amino acidresidues, other protecting groups, and the nature of the particular R₃and/or R₄ group(s) ultimately being introduced. Compounds of formula (2)in which Y is bromo and protected thio are commercially available or canbe prepared utilizing materials, techniques, and procedures well knownand appreciated by one of ordinary skill in the art or described herein.See PCT Application WO 96/11209, published Apr. 8, 1996. Examplescommercially available compounds of formula (2) in which Y is bromoinclude 2-bromopropionic acid, 2-bromobutyric acid, 2-bromovaleric acid,2-bromohexanoic acid, 6-(benzoylamino)-2-bromohexanoic acid,2-bromoheptanoic acid, 2-bromooctanoic acid, 2-bromo-3-methylbutyricacid, 2-bromoisocaproic acid, 2-bromo-3-(5-imidazoyl)proionic acid,(R)-(+)-2-bromopropionic acid, (S)-(−)-2-bromopropionic acid.

For example, a compound of formula (3) is contacted in a couplingreaction with a compound of formula (2). The compound of formula (2) maybe converted to an activated intermediate; such as and acid chloride, ananhydride; a mixed anhydride of aliphatic carboxylic acid, such asformic acid, acetic acid, propionic acid, butyric acid, isobutyric acid,pivalic acid, 2-ethylbutyric acid, trichloroacetic acid, trifluoroaceticacid, and the like; of aromatic carboxylic acids, such as benzoic acidand the like; of an activated ester, such as phenol ester, p-nitrophenolester, 2,4-dinitrophenol ester, pentafluorophenol ester,pentachlorophenol ester, N-hydroxysuccinimide ester,N-hydroxyphthalimide ester, 1-hydroxy-1H-benztriazole ester,O-azabenztriazoyl-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate andthe like; activated amide, such as imidazole, dimethylpyrazole,triazole, or tetrazole; or an intermediate formed in the presence ofcoupling agents, such as dicyclohexylcarbodiimide or1-(3-dimethyaminopropyl)-3-ethylcarbodiimide. The reaction is carriedout in a suitable solvent, such as dichloromethane, chloroform,tetrahydrofuran, or dimethylformafide. The reaction generally is carriedout at temperatures of from about −20° C. to the refluxing temperatureof the solvent and generally requires 1 to 48 hours. The product can beisolated and purified by techniques well known in the art, such asfiltration, extraction, evaporation, chromatography, andrecrystallization.

In Reaction Scheme A, step 2, a compound of formula (4) in which Y ishydroxy or bromo gives rise to a compound of formula (5) in which Y isprotected thio.

A compound of formula (4) in which Y is hydroxy (obtained from protectedhydroxy compounds of formula (2)) undergoes a displacement reaction withan appropriate thio introducing reagent by the method of Mitsunobu togive a compound of formula (5) in which Y is a protected thiosubstituent. For example, a compound of formula (4) in which Y ishydroxy reacts with thioacetic acid or thiobenzoic acid,triphenylphosphine, and diethylazodicarboxylate in a suitable aproticsolvent, such as tetrahydrofuran to give a compound of formula (5) inwhich Y is thioacetyl or thiobenzoyl. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, lyophilization, chromatography, andrecrystallization.

A compound of formula (4) in which Y is bromo undergo a displacementreaction with an appropriate thio introducing reagent to give a compoundof formula (5) in which Y is protected thio substituent which gives riseupon deprotection and subsequent elaboration, if desired, the —SR₄ asdesired in the final compound of formula (1).

For example, a solution of p-methoxybenzylmercaptan in a suitableorganic solvent such as dimethylformamide is degassed and treated with asuitable base such as sodium hydride. After about 1 to 2 hours, asolution of a compound of formula (4) in which Y is bromo is added. Thereaction may benefit from the addition of a suitable catalyst, such astetra-n-butylammonium iodide. The reaction mixture is carried out for 1to 25 hours at temperatures ranging from 0° C. to about 100° C. Theproduct can be isolated and purified by techniques well known in theart, such as extraction, evaporation, trituration, lyophilization,chromatography, and recrystallization.

In Reaction Scheme A, step 3, a compound of formula (5) in which Y isprotected thio undergoes selective deprotection to give a compound offormula (6). Protected thio substituents include thioesters, such asthioacetyl or thiobenzoyl, thioethers, such as thiobenzyl,thio-4-methoxybenzyl, thiotriphenylmethyl, or thio-t-butyl, orunsymmetrical sulfides, such as dithioethyl or dithio-t-butyl. The useand selective removal of thio protecting groups is well known andappreciated in the art and described in Protective Groups in OrganicSynthesis, Theodora W. Greene (Wiley-Interscience, 2nd Edition, 1991).

Alternately, in Reaction Scheme A, step 4, a compound of formula (4) inwhich Y is protected thio is selectively deprotected to give a compoundof formula (6), as described above, in Reaction Scheme A, step 3.

In Reaction Scheme A, step 5, a compound of formula (6) undergoes aundergoes modification reaction to give a compound of formula (7). Suchmodification reactions include, thiol esterification and disulfideformation.

Compounds of formula (7) in which R₄ is —C(O)R₁₀ or —C(O)—(CH₂)_(q)—Xgroup can be synthesized by thiol esterifications according totechniques well known and appreciated by one of ordinary skill in theart, such as those disclosed in U.S. Pat. No. 5,424,425, issued Jun. 13,1995.

For example, in a thiol esterification a compound of formula (6) iscontacted with about an equimolar amount of an appropriate acid, such asHO—C(O)R₁₀ or HO—C(O)—(CH₂)_(q)—X in the presence of a suitable couplingagent to give a compound of formula (6) in which R₄ is —C(O)R₁₀ or—C(O)—(CH₂)_(q)—X. The reaction is carried out in the presence of acoupling agent such as 2-fluoro-1-methylpyridinium p-toluenesulfate,(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride),carbonyldiimidazole, (1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, ordiethylcyanophosphonate in a suitable aprotic solvent such as methylenechloride. The reaction is generally carried out at temperature ofbetween −20° C. and the boiling point of the solvent. Generally, thereaction requires 1 to 24 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, lyophilization, chromatography, andrecrystallization.

Compounds of formula (7) in which R₄ is —S-G group can be synthesizedaccording to techniques well known and appreciated by one of ordinaryskill in the art, as disclosed in PCT Application No. WO 95/21839,published Aug. 17, 1995 and U.S. Pat. No. 5,491,143, issued Feb. 13,1996, and U.S. Pat. No. 5,731,306, issued Mar. 24, 1998, and Roques, B.P. et al., J. Med. Chem. 33, 2473-2481 (1992).

For example, in a disulfide formation a compound of formula (6) iscontacted with an appropriate compound of formula (8).

An appropriate compound of formula (8) is one which gives G as desiredin the final product of formula (1) or gives rise upon deprotection to Gas is desired in the final product of formula (1). In addition, thecompound of formula (8) may have stereochemistry as desired in the finalproduct of formula (1). The reaction is carried out in a suitablesolvent, such as ethanol, methanol, dichloromethane, or mixtures ofethanol or methanol and dichlorornethane. The solvent is degassed bypassing a stream of nitrogen gas through it for 15 minutes before thereaction is carried out. The reaction is carried out using from 1.0 to4.0 molar equivalents of an appropriate compound of formula (8). Thereaction is carried out at temperatures of from 0° C. to the refluxingtemperature of the solvent, with a temperature of 10° C. to 30° C. beingpreferred. The reaction generally requires from 1 to 48 hours. Theproduct can be isolated by techniques well known in the art, such asextraction, evaporation, and precipitation and can be purified bychromatography and recrystallization.

In Reaction Scheme A, step 6, a compound of formula (4) in which Y ishydroxy or bromo is displaced by an appropriate thiol, HSR₄, by themethods described in Reaction. Scheme A, step 2, to give a compound offormula (7). In Reaction Scheme A, step 6, an appropriate thiol HSR₄ isone which gives R₄ as desired in the final product of formula (1) orgives rise to R₄ as desired in the final product of formula (1). Also inReaction Scheme A, step 6, a compound of formula (4) in which Y is bromocan be displaced by an appropriate thio ester, Ph₃S—C(O)—(CH₂)_(q)—X bytechniques well known and appreciated in the art, as disclosed in U.S.Pat. No. 5,424,425, issued Jun. 13, 1995.

In Reaction Scheme A, a compound of formula (5), (6), or (7) isoptionally deprotected to give a compound of formula (1). Suchdeprotection reactions are well known appreciated in the art and mayinclude selective deprotections of protecting groups on A′, R₁, R₂, R₃,and R₄, as required to give the desired compound of formula (1).

In Reaction Scheme B, step 1, an appropriate compound of formula (5) isdeprotected, hydrolyzed, or reduced to give a compound of formula (9).In Reaction Scheme B, step 1, an appropriate compound of formula (5) isone in which A′ is A or gives rise to A upon deprotection andmodification, if desired, in the final product of formula (1) and R₁,and R₂ are as desired in the final product of formula (1) or give riseupon deprotection to R₁ and/or R₂ as desired in the final product offormula (1). In Reaction Scheme B, step 1, an appropriate compound offormula (5) is one in which R_(3′) gives rise to a compound of formula(9) in which R_(3″) is R₃ as desired in the final product of formula (1)or undergoes flirter derivitization (step 2) to give a compound offormula (10) in which R₃ is as desired in the final product of formula(1). In Reaction Scheme B, step 1, an appropriate compound of formula(5) is one in which Y is —SR₄ as desired in the final compound offormula (1) or Y gives rise upon deprotection (step 3) and furtherfunctionalization (step 4) or deprotection (step 5) to give —SR₄ asdesired in the final product of formula (1). In Reaction Scheme B, theuse of compounds of formula (5) in which Y is a protected thio group,such as thioacetyl, thiobenzoyl, 4-methoxybenzylthio or t-butylthio ispreferred.

For example, in a deprotection a compound of formula (5) in which R_(3′)is —(CH₂)_(m)—W (phthalimido group) is contacted with a molar excess ofhydrazine monohydrate to give a compound of formula (9) in which R_(3″)is —(CH₂)_(m)—NHR₈ in which R₈ is hydrogen. The reaction is typicallycarried out in a protic organic solvent, such as methanol or ethanol.The reaction is generally carried out at room temperature for a periodof time ranging from 5-24 hours. The product can be isolated bytechniques well known in the art, such as extraction, evaporation, andprecipitation and can be purified by chromatography andrecrystallization.

Alternately, for example, in a deprotection of a compound of formula (5)in which R_(3′) is —(CH₂)_(m)—NR₈-t-Boc is contacted with a molar excessof a suitable acid to give a compound of formula (9) in which R_(3″) is—(CH₂)_(m)—NHR₈. The reaction is typically carried out in a organicsolvent, such as methanol, ethanol, ethyl acetate, diethyl ether, ordioxane. Suitable acids for this reaction are well known in the art,including hydrochloric acid, hydrobromic acid, trifluoroacetic acid, andmethanesulfonic acid. The Keaction is generally carried out attemperatures from about 0° C. to about room temperature for a period oftime ranging from 1-10 hours. The product can be isolated by techniqueswell known in the art, such as extraction, evaporation, andprecipitation and can be purified by chromatography andrecrystallization.

For example, in a hydrolysis a compound of formula (5) in which R_(3′)is —(CH₂)_(m)—C(O)OPg₃ and Pg₃ is methyl or ethyl is contacted withabout 1 to 2 molar equivalents of lithium hydroxide, sodium hydroxide,or potassium hydroxide to give a compound of formula (9) in which R_(3″)is —(CH₂)_(m)—CO₂H. The reaction is carried out in a suitable solvent,such as methanol, ethanol methanol/water mixtures, ethanol/watermixtures, or tetrahydrofuran/water mixtures and generally requires 1 to24 hours. The reaction is carried out at temperatures of from about 0°C. to the refluxing temperature of the solvent. The resulting acid isisolated and purified by techniques well known in the art, such asacidification, extraction, evaporation, and precipitation and can bepurified by trituration, precipitation, chromatography, andrecrystallization.

For example, in a reduction a compound of formula (5) in which R_(3′) is—(CH₂)_(m−1)—CO₂Pg₃ in which Pg₃ is methyl or ethyl is contacted with asuitable reducing agent, such as lithium borohydride, lithium aluminumhydride, diisobutylaluminum hydride, 9-borabicyclo(3.3.1)nonane,preferably lithium borohydride to provide a compound of formula (9) inwhich R_(3″) is —(CH₂)_(m−1)—CH₂OH. The reaction is carried out in asuitable solvent, such as dichloromethane, tetrahydrofuran, or toluene,with tetrahydrofuran being preferred. The reaction is carried out at atemperature of from about −30° C. to about 50° C. and generally requiresfrom 2 to 12 hours. The product can be isolated by quenching,extraction, evaporation, and precipitation and can be purified bytrituration, chromatography, and recrystallization.

In Reaction Scheme B, step 2, a compound of formula (9) undergoes aderivitization reaction to give a compound of formula (10) in which R₃is as desired in the final product of formula (1). Such derivitizationreactions include hydrolysis of esters and ester formations as are wellknown in the art, ether formation, amine alkylation, formation ofamides, urea formation, carbamate formation, and formation ofsulfonamide.

For example, in an ether formation a compound of formula (9) in whichR_(3″) is —(CH₂)_(m−1)—CH₂OH is contacted with 1 to 10 molar equivalentsof a suitable akylating agent to give a compound of formula (10) inwhich R₃ is —(CH₂)_(m)-Z-Q in which Z is —O—. A suitable alkylatingagent is one which transfers Q or protected Q as desired in the finalproduct of formula (1), such as benzyl bromide, benzyl chloride,substituted benzyl bromide, substituted benzyl chloride, ethylbromoacetate, t-butyl bromoaceate, ethyl 3-chloropropionate, ethyl3-bromopropionate, ethyl 5-bromovalerate, ethyl 4-bromobutyrate,3-chloropropionamide, 2-bromoethylbenzene, substituted2-bromoethylbenzene, 1-chloro-3-phenylpropane, 1-bromo-4-phenylbutane,and the like, or nitrogen mustards, including 2-dimethylaminoethylchloride, 2-diethylaminoethyl chloride, and 3-dimethylaminopropylchloride. The reaction is carried out in a suitable solvent, such asdiethyl ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide,or acetonitrile and using a suitable base, such as sodium hydride,potassium hydride, potassium t-butoxide, and lithium diisopropylamide.The reaction is generally carried out at temperatures of −70° C. androom temperature and require from about 1-24 hours. The product can beisolated by techniques well known in the art, such as extraction,evaporation, and precipitation and can be purified by chromatography andrecrystallization.

Alternately, as appreciated by those skilled in the art, an etherformation can also be carried out by a procedure similar to the oneabove using a compound of formula (9) in which R_(3″) is—(CH₂)_(m−1)—CH₂OH in which the hydroxy group is first converted to aleaving group, such as chloro, bromo, or mesylate and a suitable alcoholwhich transfers Q or protected Q as desired in the final product offormula (1), such as benzyl alcohol, substituted benzyl alcohol, phenol,substituted phenol, and the like. The conversion of hydroxy to leavinggroups, such as chloro, bromo, and mesylate are well known andappreciated in the art.

For example, in an amine alkylation a compound of formula (9) in whichR_(3″) is —(CH₂)_(m)—NHR₈ is contacted with 1 to 10 molar equivalents ofa suitable akylating agent to give a compound of formula (10) in whichR₃ is —(CH₂)_(m)-Z-Q in which Z is —NR₈—. The reaction may be carriedout after protection of the amine function of R_(3″) in which R₈ ishydrogen by a suitable protecting group, such as benzyl or t-Boc. For anamine alkylation a suitable alkylating agent is one as described abovefor the ether formation and also includes alkylhalides, such as methyliodide, methyl bromide, ethyl bromide, propyl bromide, propyl chloride,butyl bromide, butyl chloride, and the like. The reaction is carried outin a suitable solvent, such as methanol, ethanol, dimethylformamide, orpyridine and using a suitable base, such as sodium carbonate,triethylamine, N,N-diisopropylethylamine or pyridine. The reaction isgenerally carried out at temperatures of room temperature to therefluxing temperature of the solvent and require from about 1-24 hours.The product can be isolated by techniques well known in the art, such asextraction, evaporation, and precipitation and can be purified bychromatography and recrystallization.

Alternately, for example, in an amine alkylation a compound of formula(9) in which R_(3″) is —(CH₂)_(m)—NH₂ is contacted in a reductivealkylation with a suitable aldehyde to give a compound of formula (10)useful as an intermediate for preparing compounds in which R₃ is—(CH₂)_(m)-Z-Q in which Z is —NR₈—. A suitable aldehyde is one whichtransfers Q or protected Q as desired in the final product of formula(1), such as benzaldehyde and substituted benzaldehydes. The reaction iscarried out in a suitable solvent, such as methanol, ethanol,tetrahydrofuran, or mixtures of methanol or ethanol and tetrahydrofuran.The reaction may be carried out in the presence of a drying agent, suchas sodium sulfate or molecular sieves. The reaction is carried out inthe presence of from 1.0 to 6.0 molar equivalents of a suitable reducingagent, such as, sodium borohydride or sodium cyanoborohydride withsodium cyanoborohydride being preferred. It may be advantageous tomaintain the pH in the range of about 4 to 6. The reaction is generallycarried out at temperatures of from 0° C. to the refluxing temperatureof the solvent. Generally, the reactions require 1 to 72 hours. Theproduct can be isolated by techniques well known in the art, such asextraction, evaporation, and precipitation and can be purified bychromatography and recrystallization.

For example, in an amido formation a compound of formula (9) in whichR_(3″) is is —(CH₂)_(m)—CO₂H is contacted with a suitable amine in anamide formation to give a compound of formula (10) in which R₃ is—(CH₂)_(m)-Z-Q in which Z is amido. Such amide formation reactions usingcarboxy activation or suitable coupling agents are well known in the artand described above. A suitable amine, HNR₈Q, gives rise to R₈ and Q asdesired in the final product of formula (1), such as methylamine,ethylamine, propylamine, butylamine, N-methyl benzylamine, benzylβ-alanine, 4-(3-aminopropyl)morpholine, and the like.

For example, in an amide formation a compound of formula (9) in whichR_(3″) is is —(CH₂)_(m)—NHR₈ is contacted with a suitable carboxylicacid in an amide formation to give a compound of formula (10) in whichR₃ is —(CH₂)_(m)-Z-Q in which Z is amide. Such amide formation reactionsusing carboxy activation or suitable coupling agents are well known inthe art and described above. Suitable carboxylic acids, QC(O)—OH, areones give rise to Q as desired in the final product of formula (1), suchas benzoic acid, substituted benzoic acids, phenyl acetic acids,substituted phenylacetic acids, mono-t-butyl malonate, and the like.

For example, in a urea formation a compound of formula (9) in whichR_(3″) is is —(CH₂)_(m)—NHR₈ is contacted with an appropriateisocyanate, O═C═N-Q, to give a compound of formula (10) in which R₃ is—(CH₂)_(m)-Z-Q in which Z is urea. An appropriate isocyanate is onewhich gives rise to Q as desired in the final product, such as phenylisocyanate, substituted phenyl isocyanate, napthyl isocyanate, ethylisocyanatoacetate, and the like. The reaction is carried out by addingan equivalent of, or a slight molar excess of, an appropriate isocyanateis added to a solution of a compound of formula (9) in which R_(3″) is—(CH₂)_(m)—NHR₈ in a suitable solvent, such as diethyl ether, benzene,or toluene. The reaction is carried out at temperature of from about 0°C. to the refluxing temperature of the solvent and require about 1-24hours. The product can be isolated and purified by techniques well knownin the art, such as filtration, extraction, evaporation, trituration,chromatography, and recrystallization.

For example, in an N-carbamoyl formation a compound of formula (9) inwhich R_(3″) is —(CH₂)_(m)—NHR₈ is contacted with an appropriatechloroformate to give a compound of formula (10) in which R₃ is—(CH₂)_(m)-Z-Q in which Z is N-carbamoyl. An appropriate chloroformateis one which gives rise to Q as desired in the final product of formula(1). Examples of chloroformates include benzyl chloroformate, naphthylchloroformate, phenyl chloroformate, and substituted phenylchloroformates, such as 4-chlorophenyl chloroformate, 4-methylphenylchloroformate, 4-bromophenyl chloroformate, 4-fluorophenylchloroformate, 4-methoxyphenyl chloroformate and the like. The reactionis carried out by adding an equivalent of, or a slight molar excess of,an appropriate chloro formate to a solution of a compound of formula (9)in which R_(3″) is —(CH₂)_(m)—NHR₈ in a suitable solvent, such astoluene, tetrahydrofuran, dimethylformamide, dichloromethane, pyridine,or chloroform. The reaction is carried out in the presence of an excessof a suitable base, such as triethylamine, sodium carbonate, potassiumbicarbonate, pyridine or N,N-diisopropylethylamine. The reaction iscarried out at a temperature of from −70° C. to the refluxingtemperature of the solvent and generally requires from 30 minutes to 24hours. The product can be isolated and purified by techniques well knownin the art, such as extraction, evaporation, chromatography, andrecrystallization.

For example, in an O-carbamoyl formation a compound of formula (9) inwhich R_(3″) is

—(CH₂)_(m−1)—CH₂OH is contacted with an appropriate isocyanate, asdefined above for urea formation, to give a compound of formula (10) inwhich R₃ is —(CH₂)_(m)-Z-Q in which Z is O-carbamoyl. The reaction iscarried out in a suitable solvent, such as diethyl ether,tetrahydrofuran, dimethylformamide, or acetonitrile. The reaction may befacilitated by the use of catalytic amount of a suitable base, such assodium hydride, potassium hydride, or potassium t-butoxide. The reactionis generally carried out at temperatures of from −20° C. to roomtemperature and require from about 1-24 hours. The product can beisolated by techniques well known in the art, such as extraction,evaporation, and precipitation and can be purified by chromatography andrecrystallization.

For example, in a sulfonamide formation to prepare a compound in whichR₃ is —(CH₂)_(m)—NR_(8′)SO₂—Y₁, a compound of formula (9) in whichR_(3″) is —(CH₂)_(m)—NHR₈ is contacted with an appropriate sulfonamideforming reagent. An appropriate sulfonamide forming reagent, such as asulfonyl chloride, Y₁S(O)₂Cl, or sulfonyl anhydride, Y₁(O)₂S—O—S(O)₂ Y₁,is one which gives rise to Y₁ as desired in the final product. Examplesof appropriate sulfonamide forming reagents are, benzenesulfonylchloride, dansyl chloride, N-morpholinylsulfonyl chloride,N-piperidinylsulfonyl chloride, 2,4,5-trichlorobenzenesulfonyl chloride,2,5-dichlorobenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonylchloride, 2-mesitylenesulfonyl chloride, 4-bromobenzenesulfonylchloride, 4-fluorobenzenesulfonyl chloride, 4-chlorobenzenesulfonylchloride, 4-methoxybenzenesulfonyl chloride, 4-t-butylbenzenesulfonylchloride, p-toluenesulfonyl chloride, 2,3,4-trichlorobenzenesulfonylchloride, 2,5-dimethoxybenzenesulfonyl chloride, 4-ethylbenzenesulfonylchloride, 3,4-dimethoxybenzenesulfonyl chloride,2,6-dichlorobenzenesulfonyl chloride, 3-bromobenzenesulfonyl chloride,4-n-butylbenzenesulfonyl chloride, benzenesulfonic anhydride,4-toluenesulfonic anhydride, and 2-mesitylenesulfonic anhydride. Thereaction is carried out in a suitable solvent, such as tetrahydrofuran,dichloromethane, pyridine, or chloroform and in the presence of anexcess of a suitable base, such as triethylamine, sodium carbonate,pyridine, or N,N-diisopropylethylamine. The reaction is carried out at atemperature of from −50° C. to the refluxing temperature of the solventThe reaction generally requires from 30 minutes to 24 hours. The productcan be isolated and purified by techniques well known in the art, suchas extraction, evaporation, chromatography, and recrystalation.

In Reaction Scheme B, optional step 3, a compound of formula (10) inwhich R₃ is as desired in the final product of formula (1) undergoes aselective thiol deprotection to give a compound of formula (11). Suchselective thiol deprotections using suitable protecting groups are wellknown and appreciated in the art as discussed in Reaction Scheme A, step4, above.

In Reaction Scheme B, step 4, a compound of formula (11) undergoes amodification reaction as described in Reaction Scheme A, step 5, above,to give a compound of formula (7).

In Reaction Scheme B, optional step 5, a compound of formula (10), (11),or (12) is deprotected to give a compound of formula (1) as discussed inReaction Scheme A, above.

Alternate routes for preparing the compounds of formula (2) in which Yis bromo are presented in Reaction Schemes C.1 and C.2.

In Reaction Scheme C.1, an appropriate α-amino carboxylic acid offormula (20) is deaminobrominated to give a compound of formula (2) inwhich Y is bromo. An appropriate α-amino carboxylic acid of formula(20), and protected forms thereof, is one which is one in which R_(3′)is as described above in Reaction Scheme A, step 8, above. In addition,α-amino carboxylic acid of formula (20) may also be one in which thestereochemistry at the R_(3′) bearing carbon gives rise afterdisplacement to the stereochemistry as desired at that carbon in thefinal product of formula (1). Such appropriate α-amino carboxylic acidof formula (20), are commercially available or may be readily preparedby techniques and procedures well known and appreciated by one ofordinary skill in the art. For example, L-alanine, D-alanine, L-valine,D-valine, D-norvaline, L-leucine, D-leucine, D-isoleucine,D-tert-leucine, glycine, L-glutamic acid, D-glutamic acid, L-glutamine,D-glutamine, L-lysine, D-lysine, L-ornithine, D-ornithine,(D)-(−)-2-aminobutyric acid, D-threonine, D-homoserine, D-allothreonine,D-serine, D-2-aminoadipic acid, D-aspartic acid, D-glutamic acid,D-lysine hydrate, 2,3-diaminopropionic acid monohydrobromide,D-ornithine hydrochloride, D,L-2,4-diaminobutyric acid dihydrochloride,L-meta-tyrosine, D-4-hydroxyphenylglycine, D-tyrosine, L-phenylalanine,D-phenylalanine, D,L-2-fluorophenylalanine,beta-methyl-D,L-phenylalanine hydrochloride, D,L-3-fluorophenylalanine,4-bromo-D,L-phenylaline, L-phenylalanine, L-phenylglycine,D-phenylglycine, D,L-4-fluorophenylalanine, 4-iodo-D-phenylalanine,D-homophenylalanine, D,L-2-fluorophenylglycine,D,L-4-chlorophenylalanine, and the like, are all commercially availableand the methods in D. A. Evans, et al. J. Am. Chem. Soc., 112, 4011-4030(1990); S. Ikegami et al. Tetrahedron, 44, 5333-5342 (1988); W. Oppolzeret al. Tet. Lets. 30, 6009-6010 (1989); Synthesis of Optically Activeα-Amino-Acids, R. M. Williams (Pergamon Press, Oxford 1989); M. J.O'Donnell ed.: α-Amino-Acid Synthesis, Tetrahedron Symposia in print,No. 33, Tetrahedron 44, No. 17 (1988); U. Schöllkopf; PureAppl. Chem.55, 1799 (1983); U. Hengarter et al. J. Org. Chem., 44, 3748-3752(1979); M. J. O'Donnell et al. Tet. Lets., 2641-2644 (1978); M. J.O'Donnell et al. Tet. Lets. 23, 4255-4258 (1982); M. J. O'Donnell et al.J. Am. Chem. Soc., 110, 8520-8525 (1988).

The deaminobromination described in Reaction Scheme C.1 can be performedutilizing conditions described in Compagnone, R. S. and Rapoport, H., J.Org. Chem., 51, 1713-1719 (1986); U.S. Pat. No. 5,322,942, issued Jun.21, 1994; Overberger, C. G. and Cho, I., J. Org. Chem., 33, 3321-3322(1968); or Pfister, K. et al., J. Am. Chem. Soc., 71, 1096-1100 (1949).

For example, an α-amino carboxylic acid of formula (20) and a suitablebromide, such as hydrogen bromide or potassium bromide in acidicsolution, such as sulfric acid, is treated with sodium nitrite. Thereaction temperature is carried out a temperatures of from about −25° C.to about ambient temperature and require about 1 to 5 hours. The productcan be isolated and purified by techniques well known in the art, suchas acidification, extraction, evaporation, chromatography, andrecrystallization to give the compound of formula (11)in which Y isbromo. The product can be isolated and purified by techniques well knownand appreciated in the art, such as acidification, basification,filtration, extraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme C.2, an appropriate carboxylic acid of formula (21)is brominated to give compound of formula (2) in which Y is bromo. Anappropriate carboxylic acid of formula (21), and protected formsthereof, is one which is one in which R_(3″) is as defined in ReactionScheme A, step 8, above. In addition, carboxylic acid of formula (21)may also be one in which the stereochemistry at the R_(3′) bearingcarbon gives rise after displacement to the stereochemistry as desiredat that carbon in the final product of formula (1).

For example, a mixture of a carboxylic acid of formula (21) and dry redphosphorous are treated dropwise with bromine at temperature rangingfrom about −20° to about 10° C. The reaction mixture is then warmed toroom temperature and then heated to about 80° C. for about 2-5 hours.The reaction mixture is then cooled to room temperature, poured intowater containing sodium bisulfite, and neutralized using solid sodiumcarbonate. The aqueous layer is extracted and acidified with a suitableacid, such as concentrated hydrochloric acid. The precipitate iscollected by filtration and dried to give the compound of formula (2) inwhich Y is bromo. The product can be isolated and purified by techniqueswell known and appreciated in the art, such as acidification,basification, filtration, extraction, evaporation, trituration,chromatography, and recrystallization.

Compounds of formula (20) and (21) in which R_(3′) is a —(CH₂)_(m)—W foruse in Reaction Schemes C.1 and C.2 are prepared according to ReactionScheme D.1 and D.2.

In Reaction Scheme D.1 an appropriate ω-amino carboxylic acid of formula(22) is converted to an compound of formula (21) in which R_(3′) isW—(CH₂)_(m)—. An appropriate ω-amino carboxylic acid of formula (2) isone in which m is as desired in the final product of formula (1) and arereadily available in the art. For example, the reaction is carried outin a suitable polar solvent, such as water, ethanol, diethyl ether,tetrahydrofuran, or a water/ethanol solvent mixture using a suitablebase, such as sodium carbonate and N-carbethoxyphthalimide. The reactionmixture is typically stirred at about ambient temperature for 1-5 hours.The product can be isolated and purified by techniques well known in theart, such as acidification, extraction, evaporation, chromatography, andrecrystallization to give the desired compound of formula (21) in whichR_(3′) is W—(CH₂)_(m)—.

Reaction Scheme D.2, step 1, an appropriate α,ω-diamino acid of formula(23) undergoes, a selective N-α-protection to give anN-α-protected-ω-diamino acid of formula (24). An appropriate α,ω-diaminoacid of formula (23) is one in which m is as desired in the finalproduct of formula (1).

For example, a selective N-α-protection of a suitable α,ω-diamino acid,such as L-lysine (formula (23) in which m is 4), is accomplished bymasking the ω-amino group by formation of a benzylidene imine. Thebenzylidene imine is formed by dissolving L-lysine monohydrochloride inlithium hydroxide and cooling the solution to a temperature ranging fromabout 0° to 10° C. Freshly distilled benzaldehyde is then added and thesolution is shaken. N-ω-benzylidene-L-lysine is recovered by filtrationand evaporation. The α-amino group of the N-ω-benzylidene-L-lysine thenundergoes protection, such as the introduction of a Cbz or t-Boc group,followed by hydrolytic cleavage of the imine in situ to giveN-α-benzyloxy-carbonyl-L-lysine. Accordingly, N-ω-benzylidene-L-lysineis added to a mixture of sodium hydroxide and ethanol, cooled to atemperature of from about −5° to about

−25° C. Then, precooled solutions of benzyloxycarbonyl chloride in asolvent, such as ethanol, is added to the reaction mixture. Thetemperature is maintained in a range of from about −10° to about −25° C.during the course of addition, and may allowed to rise afterwards. Thereaction mixture is then acidified using a suitable acid, such asprecooled hydrochloric acid, and N-α-benzyloxycarbonyl-L-lysine, whichcorresponds to formula (24) where m is 4, is recovered by filtrationevaporate and recrystallization.

In Reaction Scheme D.2, step 2, N-α-benzyloxycarbonyl-L-lysine or othercompounds of formula (24) is converted toω-phthalimido-α-benzyloxycarbonyl-L-lysine or otherω-phthalimido-α-aminoprotected carboxylic acid of formula (25) by themethod described in Reaction Scheme D.1, above.

In Reaction Scheme D.2, step 3, the ω-phthalimido-α-aminoprotectedcarboxylic acid of formula (25) is deprotected to give compound offormula (20) in which R_(3′) is W—(CH₂)_(m)—.

For example, ω-phthalimido-α-benzyloxycarbonyl-L-lysine is contactedwith hydrogen in the presence of a hydrogenation catalyst, such as 10%palladium/carbon. The reactants are typically contacted in a suitablesolvent mixture such as ethanol, methanol, water, ethanol/watermixtures, or methanol/water mixtures. The reactants are typically shakenunder a hydrogen atmosphere of 35-45 psi at room temperature for aperiod of time ranging from 5-24 hours. The product is typicallyrecovered by filtration and evaporation of the solvent.

A route for preparing the compounds of formula (2) in which Y isprotected thio is presented in Reaction Scheme F. The reagents andstarting materials are readily available to one of ordinary skill in theart. In Reaction Scheme H all substituents, unless otherwise indicated,are as previously defined.

In Reaction Scheme F, step 1, a bromoacetate of formula (26) iscontacted with an appropriate thiol to give a protected acetic acidester of formula (27). In a bromoacetate of formula (26) Pg₅ is aprotecting group, such as methyl, ethyl, t-butyl, and benzyl. Anappropriate thiol is one which gives rise to a protected thio group, Y,in the product of formula (11). The use of 4-methoxybenzylmercaptan ispreferred.

For example, a bromoacetate of formula (26) is contacted with anappropriate thiol in a suitable organic solvent, such asdimethylformamide. Advantageously, the solvent is degassed. The reactionis carried out using a suitable base, such as sodium hydroxide,triethylamine, or N,N-diisopropylethylamine. The reaction is carried outat temperatures of from about −50° to about ambient temperature andrequires about 1 to 72 hours. The protected acetic acid ester of formula(27) can be isolated and purified by methods well known and appreciatedin the art, such as extraction, evaporation, chromatography, anddistillation, and recrystallization.

In Reaction Scheme F, step 2, the protected acetic acid ester of formula(27) is alkylated with an appropriate akylating agent to give a compoundof formula (28). In Reaction Scheme F, step 2, an appropriate alkylatingagent is one which transfers R_(3′) which is R₃ as desired in the finalproduct of formula (1) or gives rise after deprotection to R₃ as desiredin the final product of formula (1) or gives rise to R_(3″) as definedin Reaction Scheme B, step 1. Appropriate alkylating agents includealkylhalides, such as methyl iodide, methyl bromide, ethyl bromide,propyl bromide, propyl chloride, butyl bromide, butyl chloride, and thelike; benzyl bromide, benzyl chloride, substituted benzyl bromide,substituted benzyl chloride, ethyl bromoacetate, t-butyl bromoaceate,ethyl 3-chloropropionate, ethyl 3-bromopropionate, ethyl5-bromovalerate, ethyl 4-bromobutyrate, 3-chloropropionamide,2-bromoethylbenzene, substituted 2-bromoethylbenzene,1-chloro-3-phenylpropane, 1-bromo-4phenylbutane, and the like,N-(2-bromoethyl)phthalimide, N-(3-bromopropyl)phthalimide,N-(4-bromobutyl)phthalimide, and the like; 1-bromo-2-phenylethane,1-bromo-3-phenylpropane, 1-bromophenylbutane, and the like.

For example, a protected acetic acid ester of formula (27) is alkylatedwith an appropriate alkylating agent. The reaction is carried out in asuitable solvent, such as diethyl ether, tetrahydrofuran,dimethylformamide, and toluene using a suitable base, such as sodiumhydride, potassium hydride, potassium t-butoxide, lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, or lithium diisopropylamide. The reaction isgenerally carried out at temperatures of about −70° C. to about roomtemperature and require from about 1-24 hours. The product can beisolated by techniques well known in the art, such as extraction,evaporation, and precipitation and can be purified by chromatography andrecrystallization.

In Reaction Scheme F, step 3, the compound of formula (28) the carboxyprotecting group Pg₅ is selectively removed to give a compound offormula (3b) in which Y is protected thio. Such deprotection of estersto acids in the presence of suitable thio protecting groups are wellknown and appreciated in the art.

A general preparation of compounds of formula (3) is set forth inReaction Scheme G.

In Reaction Scheme G, step 1, an appropriate compound of structure (30)is functionalized to give the corresponding compound of structure (31).An appropriate compound of structure (30) in one in which R₂ is asdesired in the final product of formula (1).

For example, an appropriate compound of formula (30) is treatedinitially with lithium chloride and a suitable non-nucleophilic base,such as collidine in a suitable solvent such as dimethylformamide. Thisis followed by treatment with a suitable mesylating agent, such as mesylchloride. The reaction is typically carried out at a temperature rangeof from −30° C. to room temperature, preferably 0° C. and for a periodof time ranging from 2-10 hours. The product is recovered from thereaction mixture by extractive methods as are known in the art and maybe purified by chromatography.

In Reaction Scheme G, step 2, the methanesulfonate functionality of thecompound of formula (31) is eliminated and the chloro substituted withiodo to a compound of formula (32).

For example, a compound of formula (31) is treated with a suitablenon-nucleophilic base, such as potassium tert-butoxide in a suitableaprotic organic solvent, such as diethyl ether. The reaction istypically carried out at a temperature range of from −30° C. to roomtemperature, preferably 0° C. and for a period of time ranging from 15minutes to hours to give the corresponding1-chloromethyl-2-vinyl-benzene derivative which is recovered from thereaction mixture by extractive methods as are known in the art. The1-chloromethyl-2-vinyl-benzene derivative is then treated with asuitable iodinating agent, such as sodium iodide, in a suitable solvent,such as acetone. The reaction is carried out at a temperature range offrom room temperature to reflux temperature of the solvent and for aperiod of time ranging from 15 minutes to hours. The product isrecovered from the reaction mixture by extractive methods as are knownin the art.

In Reaction Scheme G, step 3, a compound of formula (32) is subjected toan addition, elimination reaction with2-(bis-methylsulfonyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo(5.2.1.01,5)dec-4-yl)-ethanone to give the corresponding compound of formula(33).

For example, the anion of2-(bis-methylsulfonyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo(5.2.1.01,5)dec-4-yl)-ethanone is formed by treating2-(bis-methylsulfonyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo(5.2.1.01,5)dec-4-yl)-ethanone with a suitable non-nucleophilic base, such asn-butyllithium in a suitable aprotic organic solvent, such astetrahydrofuran. The reaction is carried out at a temperature range offrom −78° C. to −30° C., preferable −78° C. and for a period of timeranging from 30 minutes to 2 hours. A compound of formula (32) is thenadded and the reaction is carried out at a temperature range of from−78° C. to room temperature for a period of time ranging from 1-24hours. The product is recovered from the reaction mixture by extractivemethods as are known in the art and may be purified by chromatography.

In Reaction Scheme G, step 4, a compound of formula (33) is hydrolyzedto give a compound of formula (34).

For example, a compound of formula (33) is treated with a suitable acidsuch as aqueous hydrochloric acid in a suitable organic solvent such astetrahydrofuran. The reaction is carried out at a temperature range offrom −10° C. to room temperature and for a period of time ranging from30 minutes to 20 hours. Evaporation of the solvent followed by treatmentwith inorganic base such as aqueous lithium hydroxide in a suitableorganic solvent, such as tetrahydrofuran. The reaction is carried out ata temperature range of from −10° C. to room temperature and for a periodof time ranging from 30 minutes to 10 hours. After acidification, thecorresponding 2-amino-3-(2-vinyl-phenyl)-propionic acid derivative offormula (34) was isolated by evaporation of solvents.

In Reaction Scheme G, step 5, the amino functionality of a compound offormula (34) is protected to give the corresponding compound of formula(35).

For example, a compound of formula (34) is treated with an appropriatephthalimide protecting agent, such as N-carbethoxyphthalimide in thepresence of a suitable non-nucleophilic base, such as aqueous sodiumcarbonate. The reaction is carried out at a temperature range of from−10° C. to room temperature and for a period of time ranging from 1-10hours. The product is recovered from the reaction zone by extractivemethods as are known in the art and may be purified by chromatography.

In Reaction Scheme G, step 6, the carboxylic acid functionality of acompound of formula (35) is esterified to give a compound of formula(36).

For example, a compound of formula (35) is treated with2-(trimethylsilyl)ethanol in the presence of a suitable non-nucleophilicbase, such as pyridine, in a suitable organic solvent, such astetrahydrofuran. The reaction is carried out at a temperature range offrom −30° C. to room temperature and for a period of time ranging from30 minutes to 2 hours. A coupling agent, such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) is then added andthe reaction carried out at a temperature range of from −30° C. to roomtemperature for a period of time ranging from 10-48 hours. The productis recovered from the reaction zone by extractive methods as are knownin the art and may be purified by chromatography.

In Reaction Scheme G, step 7, the vinyl functionality of a compound offormula (36) is oxidized to give a compound of formula (37).

For example, a compound of formula (36) is treated with ozone in asuitable organic solvent such as methylene chloride and methanol. Thereaction is carried out at a temperature range of from −78° C. to −50°C. and for a period of time necessary for a blue color to persist. Afterpurging the reaction with nitrogen and quenching by methods known in theart, such as addition of dimethylsulfide and pyridine, the product isrecovered from the reaction zone by extractive methods as are known inthe art and may be purified by chromatography.

In Reaction Scheme G, step 8, a compound of formula (37) is subjected toreductive amination with an appropriate amino acid, tert-butyl esterderivative to give a compound of formula (39). In Reaction Scheme G,step 8, an appropriate amino acid, tert-butyl ester derivative is one inwhich R₁ is as desired in the final product of formula (1) or gives riseto R₁ as is desired in the final product of formula (1). In addition, anappropriate amino acid, tert-butyl ester derivative is one in which thestereochemistry is as desired in the final product of formula (1). As isappreciated by those skilled in the art, the use of amino acid,tert-butyl ester derivatives give rise to compounds of formula (3) inwhich A′ is —O-tert-butyl. It is also understood that appropriate aminoacid derivatives can have a variety of carboxy substituents give rise tocompounds of formula (3) in which A′ is other than —O-tert-butyl.

For example, a compound of formula (37) is treated with an appropriateamino acid, tert-butyl ester derivative in an appropriate polar organicsolvent, such as methanol under dehydrating conditions, such asmolecular sieves. The reaction is carried out at a temperature ranged offrom −10° C. to reflux temperature of the solvent, preferably roomtemperature, and for a period of time ranging from 30 minutes to 10hours. A suitable reducing agent, such as sodium cyanoborohydride, isthen added and the reaction is carried out at a temperature range offrom −10° to reflux temperature of the solvent, preferably roomtemperature, and for a period of time ranging from 30 minutes to 24hours. The product is recovered from the reaction zone by extractivemethods as are known in art and may be purified by chromatography. Asone skill in the art would realize, those amino acid, tert-butyl esterderivatives wherein R₁ has a reactive functionality, the reactivefunctionality may be protected prior to the reductive amination reactionof step 8. The selection and utilization of suitable protecting groupsis well known by one of ordinary skill in the art and is described inProtective Groups in Organic Synthesis, Theodora W. Greene, (Wiley1981).

In Reaction Scheme G, step 9, the ester functionality of a compound offormula (39) is hydrolyzed to give a compound of formula (40).

For example, a compound of formula (39) is treated with an appropriatefluoride reagent, such as tetrabutylammonium fluoride in a suitableorganic solvent, such as tetrahydrofuran. The reaction is carried out ata temperature range of from −10° C. to room temperature and for a periodof time ranging from 30 minutes to hours. The product is recovered fromthe reaction zone by extractive methods as are known in art and may bepurified by chromatography.

In Reaction Scheme G, step 10, a compound of formula (39) is subjectedto a ring closure amination reaction to give a compound of formula (40).

For example, a compound of formula (40) is treated with a suitableactivating agent, such as isobutylchloroformate, in the presence of asuitable non-nucleophilic base, such as N-methylmorpholine in a suitableorganic solvent, such as tetrahydrofuran. The reaction is carried out ata temperature range of from −10° C. to reflux temperature of the solventand for a period of time ranging from 30 minutes to 10 hours. Theproduct is recovered from the reaction zone by evaporation and may bepurified by chromatography.

In Reaction Scheme G, step 11, the protecting group of a compound offormula (40) is removed to give a compound of formula (3) in which A′ is—O-tert-butyl as the 4-position (S)-isomer.

For example, the phthalimide protecting groups of a compound of formula(40) can be removed using hydrazine monohydrate in a suitable proticsolvent such as methanol. The reaction is carried out at a temperaturerange of from −10° C. to room temperature and for a period of timeranging from 2 hours to 4 days. The product is recovered from thereaction zone by filtration and evaporation.

The following examples present typical syntheses as described in theReaction Schemes above. These examples and preparations are understoodto be illustrative only and are not intended to limit the scope of theinvention in any way.

PREPARATION 1 Synthesis of2-(4-amino-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, tert-butyl ester

Dissolve homophthalic acid (22.2 g, 0.123 mmol) in tetrahydrofuran (250mL) and add dropwise at room temperature to a slurry of lithium aluminumhydride (15.5 g, 0.407 mol) in tetrahydrofuran (500 mL). Heat at refluxfor 18 hours, cool in an ice bath and carefully add, by dropwiseaddition, water (16 mL), followed by 50% sodium hydroxide (16 mL).Remove the ice bath, add water slowly with stirring and stir until thegray precipitate turns white and evolution of gas ceases. Filter, washsolids with methylene chloride, dry (MgSO₄) and evaporate the solvent invacuo to give 2-(2-hydroxymethyl-phenyl)-ethanol as a viscous oil (18.4g, 98%).

Mix 2-(2-hydroxymethyl-phenyl)-ethanol (12.0 g, 78.8 mmol) and collidine(23 mL, 0.17 mol) and treat with lithium chloride (7.35 g, 0.173 mmol)in dimethylformamide (125 mL). Cool in an ice bath and treat, bydropwise addition, with mesyl chloride (13.4 mL). Stir at 0° C. for 4hours, partition between ice water (300 mL) and a 1:1 mixture ofether:pentane (2×400 mL). Wash the organic layer with a saturatedsolution of CuSO₄ (2×200 mL), dry (MgSO₄) and purify by silica gelchromatography (2.5:1 hexane/ethyl acetate followed by 2:1 hexane/ethylacetate followed by 3:2 hexane/ethyl acetate) to give methanesulfonicacid 2-(2-chloromethyl-phenyl)-ethyl ester as a pale yellow oil (8.8 g,45%).

Dissolve methanesulfonic acid 2-(2-chloromethyl-phenyl)-ethyl ester (8.8g, 35.4 mmol) in ether (80 mL) and cool to −35° C. Add potassiumt-butoxide (10 g, 89 mmol) and stir for 30 minutes. Add water (50 mL)and ether (150 mL), extract, dry (Na₂SO₄) and purify by silica gelchromatography (2:3 methylene chloride/pentane) to give1-chloromethyl-2-vinyl-benzene as a colorless oil (4.43 g, 82%).

Dissolve 1-chloromethyl-2-vinyl-benzene (4.0 g, 26 mmol) in acetone (100mL) and add sodium iodide (4.5 g, 30 mmol). Heat at gentle reflux for 30minutes. Cool, add water (150 mL) and extract with pentane (200 mL). Dry(MgSO₄) and evaporate the solvent in vacuo to give1-iodomethyl-2-vinyl-benzene (95%).

Dissolve2-(bis-methylsulfanyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo(5.2.1.01,5)dec-4-yl)-ethanone (7.91 g, 21.0 mmol) in tetrahydrofuran (100 mL)and cool to −78° C. Treat, by dropwise addition, with 1.6 Mn-butyllithium in hexane (13.1 mL, 21 mmol). Stir for 1.5 hours, thenadd hexamethylphosphotriamide (HMPA) (4.25 mL, 24.4 mmol). Stir for 15minutes and add, via cannula, a solution of 1-iodomethyl-2-vinyl-benzene(6.1 g, 25 mmol) in tetrahydrofuran (100 mL). Stir overnight at roomtemperature, partition between saturated ammonium chloride (2×75 mL) andethyl acetate (400 mL). Dry (Na₂SO₄) and purify by silica gelchromatography (2.5:1 hexane/ethyl acetate) to give2-(bis-methylsulfanyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thia-4-aza-tricyclo(5.2.1.01,5)dec-4-yl)-3-(2-vinyl-phenyl)-propan-1-one as a white solid (4.5 g).

Dissolve2-(bis-methylsulfanyl-methyleneamino)-1-(10,10-dimethyl-3,3-dioxo-3-thiaffaza-tricyclo(5.2.1.01,5)dec-4-yl)-3-(2-vinyl-phenyl)-propan-1-one (5.21 g, 10.6 mmol) intetrahydrofuran (100 mL) and) and 0.75 M hydrochloric acid (100 mL).Stir at room temperature for 24 hours, evaporate the solvent in vacuo togive the hydrochloride salt as a white solid. Dissolve intetrahydrofuran (200 mL) and water (50 m), add lithium hydroxidemonohydrate (1.9 g, 4.5 mmol) and stir at room temperature under anitrogen atmosphere for 4 hours. Extract into methylene chloride (200mL) and wash with 2N sodium hydroxide (50 mL). Acidify to pH 2-3 whilecooling in an ice bath and concentrate in vacuo to give2-Amino-3-(2-vinyl-phenyl)-propionic acid as an off-white solid (3.40 g,100%).

Dissolve 2-amino-3-(2-vinyl-phenyl)-propionic acid (3.40 g) in water (75mL) and add sodium carbonate (1.97 g, 18.6 mmol) andN-carbethoxyphthalimide (2.81 g, 12.8 mmol). Stir for 2.5 hours, washwith methylene chloride (200 mL), acidify to pH 1 with cold concentratedhydrochloric acid and extract with ethyl acetate (3×200 mL), dry(Na₂SO₄), evaporate the solvent in vacuo and purify by silica gelchromatography (1:1:0.02 hexane/ethyl acetate/acetic acid) followed byrecrystallization (isopropanol) to give2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)-propionicacid as a pale yellow solid (2.47 g).

Dissolve2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)-propionicacid (2.47 g, 7.69 mmol) in tetrahydrofuran (35 mL) and cool in an icebath. Treat with pyridine (1.6 mL, 20 mmol) and2-(trimethylsilyl)ethanol (2.3 mL, 16 mmol). Stir for 30 minutes and add1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (2.21g, 11.5 mmol). Stir for 22 hours at 5° C., then at room temperature for1.5 hours. Cool to 0° C., add 0.6 times all reagents and stir at roomtemperature overnight. Dilute with ethyl acetate (150 mL), wash with 5%sulfuric acid (40 mL) and saturated sodium hydrogen carbonate (40 mL).Back extract with methylene chloride (100 mL), wash with brine (30 mL)and dry (Na2SO4). Evaporate the solvent in vacuo and purify by silicagel chromatography (2:1 hexane/ethyl acetate) to give2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)-propionicacid, 2-trimethylsilanyl-ethyl ester (2.61 g, 81%).

Dissolve2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-vinyl-phenyl)-propionicacid, 2-trimethylsilanyl-ethyl ester (2.61 g, 6.19 mmol) in methylenechloride (70 mL) and methanol (75 mL). Cool to −78° C. and treat withozone until a blue color persists. Purge with nitrogen and adddimethylsulfide (7 mL) and pyridine (0.35 mL). Allow to warm to roomtemperature gradually overnight. Partition between methylene chloride(100 mL) and water (40 mL). Extract the aqueous with methylene chloride(50 mL), dry (Na2SO4) and purify by silica gel chromatography (2.5:1hexane/ethyl acetate) to give the title compound as a colorless viscousoil (2.65 g, 100%). Step h:2-(2-(2-(1,3,-Dioxo-1,3,dihydro-isoindol-2-yl)-2-(2-trimethylsilanyl-ethoxycarbonyl)-ethyl)-benzylamino)-4-methyl-valericacid, tert-butyl ester.

Dissolve2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-formyl-phenyl)-propionicacid, 2-trimethylsilanyl-ethyl ester (250 mg, 0.590 mmol) in methanol(15 mL) and treat with L-leucine tert-butyl ester hydrochloride (0.66 g,3.0 mmol). Stir at room temperature for 2 hours with 3A molecularsieves, add sodium cyanoborohydride (0.6 mL of a 1.0M solution intetrahydrofuran, 0.6 mmol), stir for 0.5 hours, add additional sodiumcyanoborohydride (0.3 mL) and stir for 5 hours. Filter through filteraid, evaporate the solvent in vacuo and partition the residue betweenmethylene chloride (100 mL) and saturated sodium hydrogen carbonate (40mL). Dry (Na2SO4), evaporate the solvent in vacuo and purify by silicagel chromatography (5:1 hexane/ethyl acetate followed by 3:1hexane/ethyl acetate) to give2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(2-formyl-phenyl)-propionicacid, 2-trimethylsilanyl-ethyl ester (221 mg, 63%).

Dissolve2-(2-(2-(1,3-dioxo-1,3,dihydro-isoindol-2-yl)-2-(2-trimethylsilanyl-ethoxycarbonyl)-ethyl)-benzylamino)-4-methyl-valericacid, tert-butyl ester (221 mg, 0.372 mmol) in tetrahydrofuran (5 mL)and treat with tetrabutylammonium fluoride (0.43 mL of a 1.0M solutionin tetrahydrofuran, 0.43 mmol). Stir for 1.5 hours, evaporate thesolvent in vacuo and dissolve the residue in ethyl acetate (75 mL). Washwith 1N hydrochloric acid (25 mL) and brine (25 mL). Dry (Na2SO4) andevaporate the solvent in vacuo to2-(2-(2-carboxy-2-(1,3-dioxo-1,3,dihydro-isoindol-2-yl)-ethyl)-benzylamino)-4-methyl-valericacid, tert-butyl ester as a white solid (188 mg).

Dissolve2-(2-(2-carboxy-2-(1,3-dioxo-1,3,dihydro-isoindol-2-yl)-ethyl)-benzylamino)-4-methyl-valericacid, tert-butyl ester (188 mg) in tetrahydrofuran (10 mL) and cool inan ice bath. Add sequentially, N-methylmorpholine (86 μL, 0.78 mmol),and isobutylchloroformate (55 μL, 0.43 mmol). Stir for 2 hours, filter,wash salts with dry tetrahydrofuran, evaporate the solvent in vacuo andpurify by silica gel chromatography (1:1 hexane/ethyl acetate) to give2-(4-((1,3-dioxo-1,3,dihydro-isoindol-2-yl)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, tert-butyl ester as a white solid (64 mg, 93%).

Dissolve2-(4((1,3-dioxo-1,3,dihydro-isoindol-2-yl)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, tert-butyl ester (160 mg, 0.336 mmol) in methanol (3 mL) and treatwith a solution of hydrazine monohydrate (0.40 mL, 0.40 mmol) inmethanol. Stir at room temperature for 65 hours, filter through filteraid, wash with methylene chloride, filter through filter aid and dry(MgSO4). Evaporate the solvent in vacuo to give the title compound (93mg, 80.2% for this step).

EXAMPLE 12-(4-(2-Benzoylsulfanyl-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid

1.1 Synthesis of2-(4-(2-benzoylsulfanyl-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, tert-butyl ester

Dissolve2-(4-amino-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, tert-butyl ester (93 mg, 0.27 mmol) in methylene chloride (3 mL)and treat with (S)-3-phenyl-2-benzoylthiopropionic acid (115 mg, 0.40mmol) and EEDQ (100 mg, 0.40 mmol). Stir at room temperature for 18hours, evaporate the solvent in vacuo, dissolve the residue in ethylacetate (40 mL) and wash with 5% sulfuric acid (15 mL) when withsaturated sodium hydrogen carbonate (15 mL). Dry (Na₂SO₄), evaporate thesolvent in vacuo and purify by silica gel chromatography (6:1hexane/ethyl acetate followed by 2.5:1 hexane/ethyl acetate) to give thetitle compound as a colorless oil (141 mg, 85%).

1.2 Synthesis of2-(4-(2-benzoylsulfanyl-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid

Dissolve2-(4-(2-benzoylsulfanyl-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, tert-butyl ester (141 mg, 0.229 mmol) in methylene chloride (5 mL)and treat with anisole (0.12 mL, 1.15 mmol) then with trifluoroaceticacid (1.5M). Stir at room temperature for 15 hours, partition betweenethyl acetate (25 mL) and brine (15 mL). Wash the organic layer withbrine (15 mL), dry (Na₂SO₄) and purify by silica gel chromatography (1:1hexane/ethyl acetate followed by 1:1:0.01 hexane/ethyl acetate/aceticacid) to give the title compound as a white solid (157 mg).

EXAMPLE 22(4-(2-Mercapto-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid

2.1 Synthesis of2-(4-(2-mercapto-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid

Dissolve2-(4-(2-benzoylsulfanyl-3-phenyl-propionyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid (0.229 mmol) in degassed methanol (3 mL) and cool in an ice bath.Treat with degassed 1M aqueous lithium hydroxide (1.0 mL) and stir,allowing the ice bath to warm gradually over 3 hours. With the reactionat 0° C., acidify with 5% hydrochloric acid. Partition between methylenechloride (75 mL) and water (25 mL), dry (Na₂SO₄) and purify by silicagel chromatography (3:1:0.01 hexane/ethyl acetate/acetic acid followedby 1:1:0.01 hexane/ethyl acetate/acetic acid to give the title compoundas a white solid (84 mg, 80.8%).

PREPARATION 2 Synthesis of 2-bromo-6-phthalimidohexanoic acid

Combine 6-aminohexanoic acid (6-aminocaproic acid) (8.0 g, 60 mmol) andwater (100 mL). Add sodium carbonate (6.84 g, 64 mmol) andN-carbethoxyphthalimide (14.0 g, 64 mmol). After 1.5 hours, extract thereaction mixture with ethyl acetate (100 mL). Cool the aqueous layer inan ice bath and acidify using concentrated hydrochloric acid to give asolid. Collect the solid by filtration, rinse with water, and dry togive 6-phthalimidohexanoic acid (12.7 g, 80% yield).

Combine 6-phthalimidohexanoic acid (12.7 g, 48 mmol) and dry redphosphorous (1.95 g, 63 mmol). Cool in an ice bath and add dropwisebromine (12.7 mL, 246 mmol). Warm to room temperature and then heat to80° C. After 3 hours, cool the reaction mixture to ambient temperature,pour into water (300 mL) containing sodium bisulfite, and neutralizeusing solid sodium bicarbonate and extract with diethyl ether (about 150mL). Acidify the aqueous layer with concentrated hydrochloric acid givea solid. Collect the solid by filtration and dry to give the titlecompound (15 g, 91.5% yield, 73.2% for both steps).

PREPARATION 3 Synthesis of (R)-2-bromo-6-phthalimidohexanoic acid

Combine (R)-2-N-carbobenzyloxy-6-aminohexanoic acid ((R)—Na-Cbz-lysine)(14.0 g, 50 mmol) and water (500 mL). Add sodium carbonate (5.65 g, 53mmol) and N-carbethoxyphthalimide (13.15 g, 60 mmol). After 1.5 hours,acidify using concentrated hydrochloric acid to give a solid. Collectthe solid by filtration, rinse with water, and dry to give(R)-2-N-carbobenzyloxy-6-phthalamidohexanoic acid.

Combine (R)-2-N-carbobenzyloxy-6-phthalamidohexanoic acid obtainedabove, methanol (200 mL), 10% palladium-on-carbon (1 g) and treat withhydrogen at atmospheric pressure. After 18 hours, filter, add to thefiltrate a solution of hydrochloric acid in methanol (50 mL, 1 M, 50mmol), and evaporate in vacuo to give (R)-2-amino-6-phthalamidohexanoicacid hydrochloric acid salt.

Combine (R)-2-amino-6-phthalamidohexanoic acid hydrochloric acid salt(12.5 g, 40 mmol) and a 2.5 M aqueous sulfuric acid solution (40 mL).Cool in a salt-ice bath. Add 49% aqueous hydrobromic acid solution (13.2g). Add dropwise over about 20 minutes, an aqueous solution of sodiumnitrite (2.8 g, 40 mmol, in 20 mL of water). After 3 hours, warm toambient temperature. After 18 hours, collect the resultant solid byfiltration, rinse with water and dry in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 1/1 ethylacetate/dichloromethane containing 5% acetic acid to give the titlecompound.

EXAMPLE 32-(4-(2-Mercapto-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid

3.1 Synthesis of2-(4-(2-bromo-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid t-butyl ester

Combine2-(4-amino-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid, tert-butyl ester (0.34 mmol), 2-bromo-6-phthalimidohexanoic acid(0.189 g, 0.56 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.106 g, 0.55 mmol), and 1-hydroxybenztriazole hydrate((75 mg, 0.56 mmol) in dicloromethane (8 mL). After 17 hours, evapoartein vacuo to give a residue, partition the residue between ethyl aceateand an aqueous 5% sulfuric acid solution (about 20 mL). Separate thelayers, extract the organic layer with a saturate aqueiosu sodiumbicarbonate solution and then brine, dry over Na₂SO₄, filter, andevaporate in vacuo to give the title compound.

3.2 Synthesis of2-(4-(2-(p-methoxybenzylthio)-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid t-butyl ester

Combine p-methoxybenzylmercaptan (0.08 mL, 0.57 mmol) and-sodium hydride(17 mg, 60% oil dispersion, 0.42 mmol) in degassed dimethylformamide (3mL). After 1 hour, tetra-n-butylammonium iodide (about 5 mg) and2-(4-(2-bromo-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid t-butyl ester (0.27 mmol). After 20 hours, quench be the additionof a saturated aqueous ammonium chloride solution and dilute with water(about 5 mL). Extract with ethyl acetate (about 75 mL). Separate thelayers and extract the orgainc layer with brine, dry over Na₂SO₄,filter, and evaporate in vacuo to give the title compound.

3.3 Synthesis of2-(4-(2-mercapto-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid

Combine2-(4-(2-(p-methoxybenzylthio)-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-4-methyl-valericacid t-butyl ester (0.20 mmol), mercury (II) acetate (0.084 g, 0.26mmol), and anisole (0.23 mL, 2.1 mmol) in dichloromethane (6.6 mL). Coolin an ice bath and degas by repeatedly cycles of vacuum and filling thevessel with nitrogen gas. Add trifluoroacetic acid (2.5 mL). After 1hour, warm to ambient temperature. After 3 hours, purge with hydrogensulfide (gas) for about 10 minutes. Filter and evaporate in vacuo togive a residue. Repeatedly, combine the residue and carbon tetrachlorideand evaporate in vacuo to give the title compound.

PREPARATION 4 Synthesis of (L)-phenylalanine-N-methyl amidetrfuoroacetic acid salt

Combine t-Boc-(L)-phenylalanine (8.00 g, 30.2 mmol) and tetrahydrofuran(20 mL). Cool to about −30° C. and add sequentially N-methylmorpholine(3.5 mL, 32 mmol) and then isobutyl chloroformate (4.5 mL, 35 mmol).After 10 minutes, add 40% aqueous methylamine (13 mL, 380 mmol). After 2hours, concentrate the reaction mixture in vacuo, combine the evaporatedreaction mixture and dichloromethane (125 mL) and extract with anaqueous 1M hydrochloric acid solution and then a saturated aqueoussodium bicarbonate solution. Dry the organic layer over Na₂SO₄, filter,and evaporate in vacuo to give t-Boc-(L)-phenylalanine-N-methyl amide,which is used without further purification.

Combine t-Boc-(L)-phenylalanine-N-methyl amide (8.4 g, 30 mmol),methylene chloride (100 mL), and trfuoroacetic acid (20 mL). After 3hours, evaporate in vacuo to give a residue. Repeatedly, combine theresidue and carbon tetrachloride and toluene remove residualtrifluoroacetic acid by coevaporation and evaporate in vacuo to give aresidue. Triturate the residue with diethyl ether to yield the titlecompound as a solid (9.12 g, 100%).

PREPARATION 5 Synthesis of2-(4-amino-3-oxo-1,3,4,5-tetrahydro-benzoclazepin-2-yl)-3-phenyl-propionicacid, N-methyl amide

Prepare by the method of Preparation 1 using (L)-phenylalanine-N-methylamide trfuoroacetic acid salt to give the title compound.

EXAMPLE 42-(4-(2-Mercapto-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionicacid, N-methyl amide

4.1 Synthesis of2-(4-(2-bromo-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionicacid, N-methyl amide

Prepare by the method of Example 3.1 using2-(4-amino-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionicacid, N-methyl amide and 2-bromo-6-phthalimidohexanoic acid to give thetitle compound.

4.2 Synthesis of2-(4-(2-(p-methoxybenzylthio)-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionicacid, N-methyl amide

Prepare by the method of Example 3.2 using2-(4-(2-bromo-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionicacid, N-methyl amide and p-methoxybenzylmercaptan to give the titlecompound.

4.3 Synthesis of2-(4-(2-mercapto-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionicacid, N-methyl amide

Prepare by the method of Example 3.3 using2-(4-(2-(p-methoxybenzylthio)-6-phthalimidohexanoyl-amino)-3-oxo-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl)-3-phenyl-propionicacid, N-methyl amide, mercury (II) acetate, anisole, and trifluoroaceticacid to give the title compound.

The present invention provides a method of inhibiting matrixmetalloproteinase (MMP) to a patient in need thereof comprisingadministering to the patient an effective matrix metalloproteinaseinhibiting amount of a compound of formula (1).

As used herein, the term “patient” refers to warm-blooded animals ormammals, including guinea pigs, dogs, cats, rats, mice, hamsters,rabbits and primates, including humans. A patient is in need oftreatment to inhibit MMP when it would be beneficial to the patient toreduce the physiological effect of active MMP. For example, a patient isin need of treatment to inhibit MMP when a patient is suffering from adisease state characterized by excessive tissue disruption or tissuedegradation, such as, but not limited to, a neoplastic disease state orcancer, rheumatoid arthritis; osteoarthritis; cardiovascular disorders,such as atherosclerosis; corneal ulceration; dental diseases, such asgingivitis or periodontal disease; and neurological disorders, such asmultiple sclerosis; chronic inflammatory disorders, such as emphysemaand especially smoking-induced emphysema.

The identification of those patients who are in need of treatment toinhibit MMP is well within the ability and knowledge of one skilled inthe art. A clinician skilled in the art can readily identify, by the useof clinical tests, physical examination and medical/family history,those patients who are suffering from disease states characterized byexcessive tissue disruption or tissue degradation.

An “effective matrix metalloproteinase inhibiting amount” of a compoundof formula (1) is an amount which is effective, upon single or multipledose administration to the patient, in providing relief of symptomsassociated with MMP and is thus effective in inhibiting MMP-inducedtissue disruption and/or MMP-induced tissue degradation. As used herein,“relief of symptoms” of MMP-mediated conditions refers to decrease inseverity over that expected in the absence of treatment and does notnecessarily indicate a total elimination or cure of the disease. Reliefof symptoms is also intended to include prophylaxis.

An effective matrix metalloproteinase inhibiting dose can be readilydetermined by the use of conventional techniques and by observingresults obtained under analogous circumstances. In determining theeffective dose, a number of factors are considered including, but notlimited to: the species of the patient; its size, age, and generalhealth; the specific disease involved; the degree of involvement or theseverity of the disease; the response of the individual patient; theparticular compound administered; the mode of administration; thebioavailability characteristics of the preparation administered; thedose regimen selected; and the use of concomitant medication.

An effective matrix metalloproteinase inhibiting amount of a compound offormula (1) will generally vary from about 0.1 milligram per kilogram ofbody weight per day (mg/kg/day) to about 300 milligrams per kilogram ofbody weight per day (mg/kg/day). A daily dose of from about 1 mg/kg toabout 100 mg/kg is preferred.

A neoplastic disease state refers to an abnormal state or conditioncharacterized by rapidly proliferating cell growth or neoplasm.Neoplastic disease states for which treatment with a compound of formula(1) will be particularly useful include: Leukemias, such as, but notlimited to, acute lymphoblastic, chronic lymphocytic, acute myeloblasticand chronic myelocytic; Carcinomas and adenocarcinomas, such as, but notlimited to, those of the cervix, oesophagus, stomach, small intestines,colon, lungs (both small and large cell), breast and prostate; Sarcomas,such as, but not limited to, oesteroma, osteosarcoma, lipoma,liposarcoma, hemangioma and hemangiosarcoma; Melanomas, includingamelanotic and melanotic; and mixed types of neoplasias such as, but notlimited to carcinosarcoma, lymphoid tissue type, follicullar reticulum,cell sarcoma and Hodgkin's Disease. Neoplastic disease states for whichtreatment with a compound of formula (1) will be particularly preferredinclude carcinomas and adenocarcinomas, particularly of the breast,prostate and lung.

Atherosclerosis is a disease state characterized by the development andgrowth of atherosclerotic lesions or plaque. The identification of thosepatients who are in need of treatment for atherosclerosis is well withinthe ability and knowledge of one of ordinary skill in the art. Forexample, individuals who are either suffering from clinicallysignificant atherosclerosis or who are at risk of developing clinicallysignificant atherosclerosis are patients in need of treatment foratherosclerosis. A clinician of ordinary skill in the art can readilydetermine, by the use of clinical tests, physical examination andmedical/family history, if an individual is a patient in need oftreatment for atherosclerosis.

The term “chronic inflammatory disease” refers to diseases or conditionscharacterized by persistent inflammation in the absence of anidentifiable irritant or microbial pathogen. Inflammatory diseases forwhich treatment with a compound of formula (1) will be particularlyuseful include: emphysema, chronic bronchitis, asthma, and chronicinflammation, and especially smoking-induced emphysema.

In effecting treatment of a patient, a compound of formula (1) can beadministered in any form or mode which makes the compound bioavailablein effective amounts, including oral and parenteral routes. For example,the compound can be administered orally, subcutaneously,intramuscularly, intravenously, transdermally, topically, intranasally,rectally, inhalation, and the like. Oral and inhalation administrationis generally preferred. One skilled in the art of preparing formulationscan readily select the proper form and mode of administration dependingupon the disease state to be treated, the stage of the disease, andother relevant circumstances. Remington's Pharmaceutical Sciences, 18thEdition, Mack Publishing Co. (1990).

A compound of formula (1) can be administered in the form ofpharmaceutical compositions or medicaments which are made by combining acompound of formula (1) with pharmaceutically acceptable carriers orexcipients, the proportion and nature of which are determined by thechosen route of administration, and standard pharmaceutical practice.

The pharmaceutical compositions or medicaments are prepared in a mannerwell known in the pharmaceutical art. The carrier or excipient may be asolid, semi-solid, or liquid material which can serve as a vehicle ormedium for the active ingredient. Suitable carriers or excipients arewell known in the art. The pharmaceutical composition may be adapted fororal or parenteral use and may be administered to the patient in theform of tablets, capsules, suppositories, solution, suspensions, gels,ointments, aerosol or the like.

The pharmaceutical compositions may be administered orally, for example,with an inert diluent or with an edible carrier. They may be enclosed ingelatin capsules or compressed into tablets. For the purpose of oraltherapeutic administration, a compound of formula (1) may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gums and thelike. These preparations should contain at least 4% of a compound offormula (1), the active ingredient, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of the active ingredient present incompositions is such that a unit dosage form suitable for administrationwill be obtained.

The tablets, pills, capsules, troches and the like may also contain oneor more of the following adjuvants: binders such as microcrystallinecellulose, gum tragacanth or gelatin; excipients such as starch orlactose, disintegrating agents such as alginic acid, Primogel, cornstarch and the like; lubricants such as magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents suchas sucrose or saccharin may be added or a flavoring agent such aspeppermint, methyl salicylate or orange flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or a fatty oil. Otherdosage unit forms may contain other various materials which modify thephysical form of the dosage unit, for example, as coatings. Thus,tablets or pills may be coated with sugar, shellac, or other entericcoating agents. A syrup may contain, in addition to the presentcompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of acompound of the invention, but may be varied to be between 0.1% andabout 50% of the weight thereof. The amount of the active ingredientpresent in such compositions is such that a suitable dosage will beobtained. Preferred compositions and preparations are able to bedetermined by one skilled in the art.

The solutions or suspensions may also include one or more of thefollowing. adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of toxicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampules, disposable syringesor multiple dose vials made of glass or plastic.

The compounds of the present invention may also be administered byinhalation, such as by aerosol or dry powder. Delivery may be by aliquefied or compressed gas or a suitable pump system which dispensesthe compounds of the present invention or a formulation thereof.Formulations for administration by inhalation of compounds of formula(1) may be delivered in single phase, bi-phasic, or tri-phasic systems.A variety of systems are available for the administration by aerosol ofthe compounds of formula (1). Dry powder formulations are prepared byeither pelletizing or milling the compound of formula (1) to a suitableparticle size or by admixing the pelletized or milled compound offormula (1) with a suitable carrier material, such as lactose and thelike. Delivery by inhalation includes the necessary container,activators, valves, subcontainers, and the like. Preferred aerosol anddry powder formulations for administration by inhalation can bedetermined by one skilled in the art.

The selective MMP-12 inhibitors of the present invention can beevaluated by the procedures that follow.

EXAMPLE A

Source and Activation of proMMP-1

ProMMP-1 (EC 3.4.24.7; interstitial collagenase) was purified fromculture medium of human rheumatoid synovial fibroblasts stimulated withmacrophage-conditioned medium according to Okada, Y. et al., J. Biol.Chem. 261, 14245-14255 (1986). The active MMP-1 was obtained bytreatment of proMMP-1 with trypsin (5 μg/mL) at 37° C. for 30 minutes,followed by addition of soybean trypsin inhibitor (50 μg/mL).

Determination of Inhibition Constant (K_(i)) for MMP-1

The activated MMP-1 is assayed using a fluorogenic substrate,Mca—Pro—Leu—Gly—Leu—Dpa—Ala—Arg—NH₂, Knight, C. G. et al., FEBS Lett.296, 263-266 (1992), at 37° C. in 2.0 mL of assay buffer containing 50mM Tris, pH 7.6, 0.2 M sodium chloride, 50 mM calcium chloride, and0.02% Brij-35. The increase in fluorescence due to cleavage of Gly—Leupeptide bond by MMP-3 was monitored with Perkin-Elmer LS50B Fluorimeter(λ_(ex) 328 nm, λ_(em) 393 nm, excitation slit 2.5, emission slit 10).Substrate and inhibitor stock solutions were made in DMF. Fordetermination of K_(i) values for MMP-1 inhibitors, a series ofintermediate inhibitor solutions were prepared in DMF and 1 or 2 μL ofthe diluted inhibitor solution was mixed with 1 μL of 2 mM substratesolution in DMF in a quartz cuvette containing 2 mL of assay buffer. Theenzyme (10 μL of 0.2 μM MMP-3 dilution in assay buffer) was added at thelast to start the reaction. For routine measurement of a K_(i) value fora reversible, competitive inhibitor, the initial rates in the presenceof at least four inhibitor concentrations (two concentrations aboveK_(i) and two concentrations below K_(i)) were measured using [S]=1 μM(<<Km) and [MMP-1]=0.8 nM. Under these conditions, the measuredK_(i, app) is close to true K_(i).

Calculation of K_(i) Values

The K_(i) for a competitive inhibitor is calculated using:v₀/v_(i)=(1+[I]/K_(i, app)) and K_(i)=K_(i, app)/(1+[S]/K_(m)), where v₀is the initial rate in the absence of inhibitor, v_(i) is the initialrate in the presence of inhibitor at the concentration of [I], [S] isthe substrate concentration, and K_(m) is the Michaelis constant. Ifslow binding is observed (i.e. if the approach to the bindingequilibrium is slow), the final steady-state rate rather than theinitial rate is taken as v_(i).

EXAMPLE B

Source and Activation of proMMP-2

Recombinant MMP-2 was purified from the fermentation broth of yeastPichia pastoris that carries the integrated MMP-2 gene into itschromosome. In brief, the full-length cDNA for MMP-2 was obtained byreverse transcription of RNA from human melanoma A375M cell line by thereverse transcriptase polymerase chain reaction (RT-PCR) using sequencespecific oligonucleotides. The nucleotide sequence was confirmed by Taqcycle sequencing. The cDNA was ligated into the Pichia pastorisexpression vector pHIL-D2 in such a way that the expression of pro-MMP-2is under the control of the methanol inducible alcohol oxidase promoter.The expression construct was digested with either SalI or NsiI and usedto transform the Pichia pastoris stains KM71 and SMD1168. A large-scaleculture of a selected clone designated 24S was performed in a high celldensity fermentor and the recombinant MMP-2 was purified from theculture supernatant by gelatin-sepharose 4B (Pharmacia). The enzyme issufficiently pure at this stage for routine measurement of inhibition.If desired, however, the enzyme may be further purified by AcA 44 gelfiltration (Spectra).

Determination of Inhibition Constant (K_(i)) for MMP-2

The active MMP-2 was obtained by activation of proMMP-2 at 37° C. for 1h with 4-aminophenylmercuric acetate which was then removed by aSephadex G-50 spin column. The enzyme is assayed using a fluorogenicsubstrate, Mca—Pro—Leu—Gly—Leu—Dpa—Ala—Arg—NH₂, at 37° C. in 2.0 mL ofassay buffer containing 50 mM Tris, pH 7.6, 0.2 M sodium chloride, 50 mMcalcium chloride, 0.02% Brij-35, and 50 μM β-mercaptoethanol. Theincrease in fluorescence is monitored (λ_(ex) 328 nm, λ_(em) 393 nm).Substrate and inhibitor stock solutions are made in DMF. The enzyme isadded at the last to start the reaction. For routine measurement of aK_(i) value for a reversible, competitive inhibitor, the initial ratesin the presence of at least four inhibitor concentrations (two inhibitorconcentrations above K_(i) and two below K_(i)) are measured using [S]=1μM (<<Km) and [MMP-2]=0.4 nM. Under these conditions, the measuredK_(i), app is close to true K_(i).

EXAMPLE C

Source and Activation of proMMP-3

ProMMP-3 (EC 3.4.24.17; Stromelysin-1) was purified from culture mediumof human rheumatoid synovial fibroblasts stimulated withmacrophage-conditioned medium according to Okada, Y. et al., J. Biol.Chem. 261, 14245-14255 (1986). The active MMP-3 was obtained bytreatment of proMMP-3 with trypsin (5 μg/mL) at 37° C. for 30 minutes,followed by addition of soybean trypsin inhibitor (50 μg/mL). Aliquotsof the activated MMP-3 were stored at −20° C.

Determination of Inhibition Constant (K_(i)) for MMP-3

The activated MMP-3 is assayed using a fluorogenic substrate,Mca—Pro—Leu—Gly—Leu—Dpa—Ala—Arg—NH₂, Knight, C. G. et al., FEBS Lett.296, 263-266 (1992), at 37° C. in an assay buffer containing 50 mM Tris,pH 7.6, 0.2 M sodium chloride, 50 mM calcium chloride, and 0.02%Brij-35. The increase in fluorescence due to cleavage of Gly—Leu peptidebond by MMP-3 was monitored with Perkin-Elmer LS50B Fluorimeter (λ_(ex)328 nm, λ_(em) 393 nm, excitation slit 2.5, emission slit 10). Substrateand inhibitor stock solutions were made in DMF and 0.1% HCl-DMF,respectively. For determination of K_(i) values for MMP-3 inhibitors, aseries of intermediate inhibitor solutions were prepared in 0.1% HCl-DMFand 1 or 2 μL of the diluted inhibitor solution was mixed with 1 μL of 2mM substrate solution in DMF in a quartz cuvette containing 2 mL ofassay buffer. The enzyme (10 μL of 0.2 μM MMP-3 dilution in assaybuffer) was added at the last to start the reaction. For routinemeasurement of a K_(i) value for a reversible, competitive inhibitor,the initial rates in the presence of at least four inhibitorconcentrations (two concentrations above K_(i) and two concentrationsbelow K_(i)) were measured using [S]=1 μM (<<Km) and [MMP-3]=1 nM. Underthese conditions, the measured K_(i), app is close to true K_(i).

Calculation of K_(i) Values

The K_(i) for a competitive inhibitor is calculated using:v_(o)/v_(i)=(1+[I]/K_(i, app)) and K_(i)=K_(i, app)/(1+[S]/K_(m)), wherev₀ is the initial rate in the absence of inhibitor, v_(i) is the initialrate in the presence of inhibitor at the concentration of [I], [S] isthe substrate concentration, and K_(m) is the Michaelis constant. Ifslow binding is observed (i.e. if the approach to the bindingequilibrium is slow), the final steady-state rate rather than theinitial rate is taken as v_(i).

EXAMPLE D

Source of MMP-12 (Macrophage Metalloelastase)

MMP-12 (EC 3.4.24.65) was cloned, expressed and purified according toShapiro, S. D. et al., J Biol. Chem. 268, 23824-23829 (1993).Autoactivation resulted in the fully processed active form of theenzyme. Aliquots of MMP-12 were stored at −70° C.

Determination of the Inhibition Constant (K_(i)) for MMP-12

The potency of inhibitors of MMP-12 was measured using either quartzcuvettes or microtiter plates. The activity of MMP-12 was measured usinga fluorogenic substrate, Mca—Pro—Leu—Gly—Leu—Dpa—Ala—Arg—NH2, Knight, C.G. et al., FEBS Lett. 296,263-266 (1992), at 25 C. in an assay buffercontaining 50 mM Tris, pH 7.6, 0.2 M sodium chloride, 50 mM calciumchloride, and 0.02% Brij-35. The increase in fluorescence due tocleavage of Gly—Leu peptide bond by MMP-12 was monitored with aPerkin-Elmer LS50B Fluorimeter (λ_(ex) 328 nm, λ_(em) 393 nm, excitationslit 2.5, emission slit 10) for the cuvette assay and with a MolecularDevices Fmax fluorescence plate reader (λex 320 nm, λλem 405 nm) for themicrotiter plate assay. Substrate and inhibitor stock solutions weremade in N,N,dimethylformamide (DMF) and 0.1% HCl-DMF, respectively.

Ki values were determined using the cuvette method by preparing a seriesof intermediate inhibitors solutions in 0.1% HCl-DMF and mixing theinhibitor with substrate (final concentration 2 μM) in a quartz cuvettecontaining 2 ml of assay buffer. MMP-12 was added to start the reactionat a concentration of 2 nM and progress curves were generated. Forroutine measurement of a Ki value for a reversible competitiveinhibitor, the initial rates in the presence of at least four inhibitorconcentrations (two concentrations above and two concentrations belowthe Ki) were measured [S]=2 μM (<<Km) and [MMP-12]=2 nM. Under theseconditions, the measured Ki,app is close to the true Ki.

Ki values were determined using the microtiter plate method in a mannersimilar to that described for the cuvette method with somemodifications. Four different inhibitor concentrations (50 μl in assaybuffer) of each compound were added to separate wells of a microtiterplate and substrate was added (100 μl) to get a final concentration of 4mM. MMP-12 was added to a final concentration of 2 nM (50 μl) to startthe reaction. Cleavage of substrate was recorded every 30 seconds for 30minutes and progress curves were generated.

Calculation of Ki Values

The Ki for a competitive inhibitor was calculated using:Vo/Vi=(1+[I]/Ki,app) and Ki=Ki,app/(1+[S]/Km), where Vo is the initialrate in the absence of inhibitor, Vi is the initial rate in the presenceof inhibitor at the concentration of [I], [S] is the substrateconcentration, and Km is the Michaelis constant. If slow binding isobserved (i.e. if the approach to the binding equilibium is slow), thefinal steady-state rate rather than the initial rate is taken as Vi.

What is claimed is:
 1. A compound of the formula

wherein Aa is —NRR′; wherein R and R′ are independently selected fromthe group consisting of hydrogen and C₁-C₆ alkyl or R and R′ takentogether with the nitrogen atom to which they are attached form aN-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; R₁ isselected from the group consisting of hydrogen, C₁-C₆ alkyl,—(CH₂)_(a)—CO₂R₅, (CH₂)_(a)C(O)NH₂, (CH₂)₄NH₂, (CH₂)₃NHC(NH)NH₂,(CH₂)₂S(O)_(b)—CH₃, CH₂OH, —CH(OH)CH₃, —CH₂—SH, —(CH₂)_(d)—Ar₁, and—CH₂—Ar₂; wherein a is 1 or 2; b is 0, 1,or 2; d is an integer from 0 to4; R₅ is selected from the group consisting of hydrogen, C₁-C₄ alkyl,and benzyl; Ar₁ is a radical selected from the group consisting of

wherein R₆ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy; R₇ is selected from the group consisting of hydrogen, halogen,C₁-C₄ alkyl, and C₁-C₄ alkoxy; Ar₂ is a radical selected from the groupconsisting of

R₂ is from 1 to 2 substituents independently selected from the groupconsisting of hydrogen, halogen, hydroxy₂ C₁-C₄ alkyl, and C₁-C₄ alkoxy;R₃ is selected from the group consisting of C₁-C₆ alkyl, (CH₂)_(m)—W,—(CH₂)_(p)—Ar₃, —(CH₂)_(k)—CO₂R₉, —(CH₂)_(m)—NR_(8′)SO₂Y₁, and—(CH₂)_(m)-Z-Q wherein m is an integer from 2 to 8; p is an integer from0-10; k is an integer from 1 to 9; W is phthalimido; Ar₃ is selectedfrom the group consisting of

wherein R₂₃ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy; R₈is hydrogen or C₁-C₆ alkyl; R₉ is hydrogen or C₁-C₆ alkyl; Y₁ isselected from the group consisting of hydrogen, —(CH₂)_(j)—Ar₄, and—N(R₂₄)₂ wherein j is 0 or 1; R₂₄ each time selected is independentlyhydrogen or C₁-C₆ alkyl or are taken together with the nitrogen to whichthey are attached to form N-morpholino, N-piperidino, N-pyrrolidino, orN-isoindolyl; Ar₄ is

wherein R₂₅ is from 1 to 3 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy; Zis selected from the group consisting of —O—, —NR₈—, —C(O)NR₈—,—NR₈C(O)—, —NR_(8′)C(O)NH—, —NR₈C(O)O—, and —OC(O)NH—; wherein R₈ ishydrogen or C₁-C₆ alkyl; Q is selected from the group consisting ofhydrogen, —(CH₂)_(n)—Y₂, and —(CH₂)_(x)Y₃; wherein n is an integer from0 to 4; Y₂ is selected from the group consisting of hydrogen,—(CH₂)_(h)—Ar₅ and —(CH₂)_(t)—C(O)OR₂₇ wherein Ar₅ is selected from thegroup consisting of

wherein R₂₆ is from 1 to 3 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy; his an integer from 0 to 6; t is an integer from 1 to 6; R₂₇ is hydrogenor C₁-C₆ alkyl; x is an integer from 2 to 4; Y₃ is selected from thegroup consisting of —N(R₂₈)₂, N-morpholino, N-piperidino, N-pyrrolidino,and N-isoindolyl; wherein R₂₈ each time taken is independently selectedfrom the group consisting of hydrogen and C₁-C₆ alkyl; R₄ is selectedfrom the group consisting of hydrogen, —C(O)R₁₀, —C(O)—(CH₂)_(q)—K and—S-G wherein R₁₀ is selected from the group consisting of hydrogen,C₁-C₄ alkyl, phenyl, and benzyl; q is 0, 1,or 2; K is selected from thegroup consisting of

wherein V is selected from the group consisting of a bond, —CH₂—, —O—,—S(O)_(r)—, —NR₂₁—, and —NC(O)R₂₂; wherein r is 0, 1,or 2; R₂₁ isselected from the group consisting of hydrogen, C₁-C₄ alkyl, and benzyl;R₂₂ is selected from the group consisting of hydrogen, —CF₃, C₁-C₁₀alkyl, phenyl, and benzyl; R₁₁ each time taken is independently selectedfrom the group consisting of hydrogen, C₁-C₄ alkyl, and benzyl; G isselected from the group consisting of

wherein w is an integer from 1 to 3; R₁₂ is selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, —CH₂CH₂S(O)_(u)CH₃, and benzyl;wherein u is 0, 1, or 2; R₁₃ is selected from the group consisting ofhydrogen, hydroxy, amino, C₁-C₆ alkyl, N-methylamino, N,N-dimethylamino,—CO₂R17, and —OC(O)R₁₈; wherein R₁₇ is hydrogen, —CH₂O—C(O)C(CH₃)₃,C₁-C₄ alkyl, benzyl, or diphenylmethyl; R₁₈ is hydrogen, C₁-C₆ alkyl orphenyl; R₁₄ is 1 or 2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen; V₁ isselected from the group consisting of —O—, —S—, and —NH—; V₂ is selectedfrom the group consisting of —N— and —CH—; V₃ is selected from the groupconsisting of a bond and —C(O)—; V₄ is selected from the groupconsisting of —O—, —S—, —NR₁₉—, and —NC(O)R₂₀—; wherein R₁₉ is hydrogen,C₁-C₄ alkyl, or benzyl; R₂₀ is hydrogen, —CF₃, C₁-C₁₀ alkyl, or benzyl;R₁₅ is selected from the group consisting of hydrogen, C₁-C₆ alkyl andbenzyl; and R₁₆ is selected from the group consisting of hydrogen andC₁-C₄ alkyl; provided that when R₂ is hydrogen, R₃ is C₁-C₆ alkyl or—(CH₂)_(p)—Ar₃ where p is 1-10 and Ar₃ is phenyl and R₂₃ is hydrogen orC₁-C₄ alkyl, and R₁ is hydrogen or C₁-C₆ alkyl, that all are notconcurrently present, or a stereoisomer, pharmaceutically acceptablesalt, or hydrate thereof.
 2. A compound according to claim 1 wherein R₁is selected from the group consisting of C₁-C₆ alkyl and —(CH₂)_(d)Ar₁.3. A compound according to claim 1 wherein R₁ is —(CH₂)_(d)Ar₁ and Ar₁is phenyl or substituted phenyl.
 4. A compound according to claim 1wherein R₄ is selected from the group consisting of hydrogen, —C(O)R₁₀and —S-G.
 5. A compound according to claim 1 wherein R₄ is hydrogen. 6.A compound according to claim 1 wherein R₄ is —C(O)R₁₀ and R₁₀ is C₁-C₄alkyl.
 7. A compound according to claim 1 wherein Aa is —NRR′ wherein Ris hydrogen and R′ is methyl.
 8. A pharmaceutical composition comprisingan effective matrix metallo-proteinases inhibitory amount of a compoundof any one of claims 1-7 in admixture or otherwise in association withone or more pharmaceutically acceptable carriers or excipients.
 9. Acompound of the formula

wherein Aa is —NRR′; wherein R and R′ are independently selected fromthe group consisting of hydrogen and C₁-C₆ alkyl or R and R′ takentogether with the nitrogen atom to which they are attached form aN-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; R₁ isselected from the group consisting of (CH₂)_(a)CO₂R₅, (CH₂)_(a)C(O)NH₂,(CH₂)₄NH₂, —(CH₂)₃—NH—C(NH)NH₂, —(CH₂)2—S(O)b—CH₃, —CH2—OH, —CH(OH)CH₃,—CH₂—SH, —(CH₂)_(d)—Ar₁, and —CH₂—Ar₂; wherein a is 1 or 2; b is 0, 1,or 2; d is an integer from 0 to 4; R₅ is selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, and benzyl; Ar₁ is a radicalselected from the group consisting of

wherein R₆ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy; R₇ is selected from the group consisting of hydrogen, halogen,C₁-C₄ alkyl, and C₁-C₄ alkoxy; Ar₂ is a radical selected from the groupconsisting of

R₂ is from 1 to 2 substituents independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁-C₄ alkyl, and C₁-C₄ alkoxy;R₃ is selected from the group consisting of C₁-C₆ alkyl, —(CH₂)_(m)—W,—(CH₂)_(p)—Ar₃, —(CH₂)_(k)—CO₂R₉, (CH₂)_(m)—NR_(8′)SO₂Y₁, and—(CH₂)_(m)-Z-Q wherein m is an integer from 2 to 8; p is an integer from0-10; k is an integer from 1 to 9; W is phthalimido; Ar₃ is selectedfrom the group consisting of

wherein R₂₃ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy;R_(8′) is hydrogen or C₁-C₆ alkyl; R₉ is hydrogen or C₁-C₆ alkyl; Y₁ isselected from the group consisting of hydrogen, —(CH₂)_(j)—Ar₄, and—N(R₂₄)₂ wherein j is 0 or 1; R₂₄ each time selected is independentlyhydrogen or C₁-C₆ alkyl or are taken together with the nitrogen to whichthey are attached to form N-morpholino, N-piperidino, N-pyrrolidino, orN-isoindolyl; Ar₄ is

wherein R₂₅ is from 1 to 3 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy; Zis selected from the group consisting of —O—, —NR₈—, —C(O)NR₈—,—NR₈C(O)—, —NR₈C(O)NH—, —NR₈C(O)O—, and —OC(O)NH—; wherein R₈ ishydrogen or C₁-C₆ alkyl; Q is selected from the group consisting ofhydrogen, —(CH₂)_(n)—Y₂, and —(CH₂)_(x)Y₃; wherein n is an integer from0 to 4; Y₂ is selected from the group consisting of hydrogen,—(CH₂)_(h)—Ar₅ and —(CH₂)_(t)—C(O)OR₂₇ wherein Ar₅ is selected from thegroup consisting of

wherein R₂₆ is from 1 to 3 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄alkoxy; his an integer from 0 to 6; t is an integer from 1 to 6; R₂₇ is hydrogenor C₁-C₆ alkyl; x is an integer from 2 to 4; Y₃ is selected from thegroup consisting of —N(R₂₈)2, N-morpholino, N-piperidino, N-pyrrolidino,and N-isoindolyl; wherein R₂₈ each time taken is independently selectedfrom the group consisting of hydrogen and C₁-C₆ alkyl; R₄ is selectedfrom the group consisting of hydrogen, —C(O)R₁₀, —C(O)—(CH₂)_(q)—K and—S-G wherein R₁₀ is selected from the group consisting of hydrogen,C₁-C₄ alkyl, phenyl, and benzyl; q is 0, 1, or 2; K is selected from thegroup consisting of

wherein V is selected from the group consisting of a bond, —CH₂—, —O—,—S(O)r, NR₂₁—, and —NC(O)R₂₂; wherein r is 0, 1, or 2; R₂₁ is selectedfrom the group consisting of hydrogen, C₁-C₄ alkyl, and benzyl; R₂₂ isselected from the group consisting of hydrogen, —CE₃, C₁-C₁₀ alkyl,phenyl, and benzyl; R₁₁ each time taken is independently selected fromthe group consisting of hydrogen, C₁-C₄ alkyl, and benzyl; G is selectedfrom the group consisting of

wherein w is an integer from 1 to 3; R₁₂ is selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, —CH₂CH₂S(O)_(u)CH₃, and benzyl;wherein u is 0, 1, or 2; R₁₃ is selected from the group consisting ofhydrogen, hydroxy, amino, C₁-C₆ alkyl, N-methylamino, N,N-dimethylamino,—CO₂R₁₇, and —OC(O)R₁₈; wherein R₁₇ is hydrogen, —CH₂O—C(O)C(CH₃)₃,C₁-C₄ alkyl, benzyl, or diphenylmethyl; R₁₈ is hydrogen, C₁-C₆ alkyl orphenyl; R₁₄ is 1 or 2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen; V₁ isselected from the group consisting of —O—, —S—, and —NH—; V₂ is selectedfrom the group consisting of —N— and —CH—; V₃ is selected from the groupconsisting of a bond and —C(O)—; V₄ is selected from the groupconsisting of —O—, —S—, —NR₁₉—, and —NC(O)R₂₀; wherein R₁₉ is hydrogen,C₁-C₄ alkyl, or benzyl; R₂₀ is hydrogen, —CF₃, C₁-C₁₀ alkyl, or benzyl;R₁₅ is selected from the group consisting of hydrogen, C₁-C₆ alkyl andbenzyl; R₁₆ is selected from the group consisting of hydrogen and C₁-C₄alkyl; or a stereoisomer, pharmaceutically acceptable salt, or hydratethereof.
 10. A pharmaceutical composition comprising an effective matrixmetalloproteinases inhibitory amount of a compound of claim 9 inadmixture of otherwise in association with one or more pharmaceuticallyacceptable carriers or excipients.
 11. A compound of the formula

wherein Aa is —NRR′; wherein R and R′ are independently selected fromthe group consisting of hydrogen and C₁-C₆ alkyl or R and R′ takentogether with the nitrogen atom to which they are attached form aN-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; R₁ isselected from the group consisting of hydrogen, C₁-C₆ alkyl,—(CH₂)_(a)—CO₂R₅, (CH₂)_(a)C(O)NH₂, —(CH₂)₄NH₂, (CH₂)₃NH—C(NH)NH₂,(CH₂)₂—S(O)_(b)—CH₃, CH₂OH, —CH(OH)CH₃, —CH₂—SH, —(CH₂)_(d)—Ar₁, and—CH₂—Ar₂; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0to 4; R₅ is selected from the group consisting of hydrogen, C₁-C₄ alkyl,and benzyl; Ar₁ is a radical selected from the group consisting of

wherein R₆ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy; R₇ is selected from the group consisting of hydrogen, halogen,C₁-C₄ alkyl, and C₁-C₄ alkoxy; Ar₂ is a radical selected from the groupconsisting of

R₂ is from 1 to 2 substituents independently selected from the groupconsisting of halogen, hydroxy, C₁-C₄ alkyl, and C₁-C₄ alkoxy; R₃ isselected from the group consisting of C₁-C₆ alkyl, —(CH₂)_(m)—W,—(CH₂)_(p)—Ar₃, (CH₂)_(k)—CO₂R₉, (CH₂)_(m)—NR_(8′)SO₂Y₁, and(CH₂)_(m)-Z-Q wherein m is an integer from 2 to 8; p is an integer from0-10; k is an integer from 1 to 9; W is phthalimido; Ar₃ is selectedfrom the group consisting of

wherein R₂₃ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy;R_(8′) is hydrogen or C₁-C₆ alkyl; R₉ is hydrogen or C₁-C₆ alkyl; Y₁ isselected from the group consisting of hydrogen, —(CH₂)1—Ar4, and—N(R₂₄)₂ wherein j is 0 or 1; R₂₄ each time selected is independentlyhydrogen or C₁-C₆ alkyl or are taken together with the nitrogen to whichthey are attached to form N-morpholino, N-piperidino, N-pyrrolidino, orN-isoindolyl; Ar₄ is

wherein R₂₅ is from 1 to 3 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy; Zis selected from the group consisting of —O—, —NR₈—, —C(O)NR₈—,—NR₈C(O)—, —NR₈C(O)NH—, —NR₈C(O)O—, and —OC(O)NH—; wherein R₈ ishydrogen or C₁-C₆ alkyl; Q is selected from the group consisting ofhydrogen, —(CH₂)_(n)—Y₂, and —(CH₂)_(x)Y₃; wherein n is an integer from0 to 4; Y₂ is selected from the group consisting of hydrogen,—(CH₂)_(h)—Ar₅ and —(CH₂)_(t)—C(O)OR₂₇ wherein Ar₅ is selected from thegroup consisting of

wherein R₂₆ is from 1 to 3 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄alkoxy; his an integer from 0 to 6; t is an integer from 1 to 6; R₂₇ is hydrogenor C₁-C₆ alkyl; x is an integer from 2 to 4; Y₃ is selected from thegroup consisting of —N(R₂₈)₂, N-morpholino, N-piperidino, N-pyrrolidino,and N-isoindolyl; wherein R₂₈ each time taken is independently selectedfrom the group consisting of hydrogen and C₁-C₆ alkyl; R₄ is selectedfrom the group consisting of hydrogen, —C(O)R₁₀, —C(O)—(CH₂)_(q)—K and—S-G wherein R₁₀ is selected from the group consisting of hydrogen,C₁-C₄ alkyl, phenyl, and benzyl; q is 0, 1, or 2; K is selected from thegroup consisting of

wherein V is selected from the group consisting of a bond, —CH₂—, —O—,S(O)_(r)—, NR₂₁—and —NC(O)R₂₂; wherein r is 0, 1, or 2; R₂₁ is selectedfrom the group consisting of hydrogen, C₁-C₄ alkyl, and benzyl; R₂₂ isselected from the group consisting of hydrogen, —CF₃, C₁-C₁₀ alkyl,phenyl, and benzyl; R₁₁ each time taken is independently selected fromthe group consisting of hydrogen, C₁-C₄ alkyl, and benzyl; G is selectedfrom the group consisting of

wherein w is an integer from 1 to 3; R₁₂ is selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, —CH₂CH₂S(O)_(u)CH₃, and benzyl;wherein u is 0,1, or 2; R₁₃ is selected from the group consisting ofhydrogen, hydroxy, amino, C₁-C₆ alkyl, N-methylamino, N,N-dimethylamino,—CO₂R₁₇, and —OC(O)R₁₈; wherein R₁₇ is hydrogen, —CH₂O—C(O)C(CH₃)₃,C₁-C₄ alkyl, benzyl, or diphenylmethyl; R₁₈ is hydrogen, C₁-C₆ alkyl orphenyl; R₁₄ is 1 or 2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen; Vi isselected from the group consisting of —O—, —S—, and —NH—; V₂ is selectedfrom the group consisting of —N— and —CH—; V₃ is selected from the groupconsisting of a bond and —C(O)—; V₄ is selected from the groupconsisting of —O—, —S—, —NR₁₉—, and —NC(O)R₂₀—; wherein R₁₉ is hydrogen,C₁-C₄ alkyl, or benzyl; R₂₀ is hydrogen, —CE₃, C₁-C₁₀ alkyl, or benzyl;R₁₅ is selected from the group consisting of hydrogen, C₁-C₆ alkyl andbenzyl; R₁₆ is selected from the group consisting of hydrogen and C₁-C₄alkyl; or a stereoisomer, pharmaceutically acceptable salt, or hydratethereof.
 12. A pharmaceutical composition comprising an effective matrixmetalloproteinases inhibitory amount of a compound of claim 11 inadmixture of otherwise in association with one or more pharmaceuticallyacceptable carriers or excipients.
 13. A compound of the formula

wherein Aa is —NRR′; wherein R and R′ are independently selected fromthe group consisting of hydrogen and C₁-C₆ alkyl or R and R′ takentogether with the nitrogen atom to which they are attached form aN-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; R₁ isselected from the group consisting of hydrogen, C₁-C₆ alkyl,—(CH₂)_(a)—CO₂R₅, (CH₂)_(a)C(O)NH₂, (CH₂)₄NH₂, (CH₂)₃NHC(NH)NH₂,(CH₂)₂S(O)_(b)—CH₃, CH₂OH, -CH(OH)CH₃, —CH₂—SH, —(CH₂)_(d)—Ar₁, and—CH₂—Ar₂; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0to 4; R₅ is selected from the group consisting of hydrogen, C₁-C₄ alkyl,and benzyl; Ar₁ is a radical selected from the group consisting of

wherein R₆ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy; R₇ is selected from the group consisting of hydrogen, halogen,C₁-C₄ alkyl, and C₁-C₄ alkoxy; Ar₂ is a radical selected from the groupconsisting of

R₂ is from 1 to 2 substituents independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁-C₄ alkyl, and C₁-C₄ alkoxy;R₃ is selected from the group consisting of —(CH₂)_(m)—W,—(CH₂)_(p)—Ar₃, —(CH₂)k-CO₂R₉, (CH₂)_(m)—NR_(8′)SO₂Y₁, and (CH₂)_(m)-Z-Qwherein m is an integer from 2 to 8; p is an integer from 0-10; k is aninteger from 1 to 9; W is phthalimido; Ar₃ is selected from the groupconsisting of

wherein R₂₃ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy;R_(8′) is hydrogen or C₁-C₆ alkyl; R₉ is hydrogen or C₁-C₆ alkyl; Y₁ isselected from the group consisting of hydrogen, —(CH₂)_(n)—Ar₄, and—N(R₂₄)₂ wherein j is 0 or 1; R₂₄ each time selected is independentlyhydrogen or C₁-C₆ alkyl or are taken together with the nitrogen to whichthey are attached to form N-morpholino, N-piperidino, N-pyrrolidino, orN-isoindolyl; Ar₄ is

wherein R₂₅ is from 1 to 3 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy; Zis selected from the group consisting of —O—, —NR₈—, —C(O)NR₈—,—NR₈C(O)—, —NR_(8′)C(O)NH—, —NR₈C(O)O—, and —OC(O)NH—; wherein R₈ ishydrogen or C₁-C₆ alkyl; Q is selected from the group consisting ofhydrogen, —(CH₂)_(n)—Y₂, and —(CH₂)_(x)Y₃; wherein n is an integer from0 to 4; Y₂ is selected from the group consisting of hydrogen,—(CH₂)_(h)—Ar₅ and —(CH₂)_(h)—C(O)OR₂₇ wherein Ar₅ is selected from thegroup consisting of

wherein R₂₆ is from 1 to 3 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄alkoxy; his an integer from 0 to 6; t is an integer from 1 to 6; R₂₇ is hydrogenor C₁-C₆ alkyl; x is an integer from 2 to 4; Y₃ is selected from thegroup consisting of —N(R₂₈)2, N-morpholino, N-piperidino, N-pyrrolidino,and N-isoindolyl; wherein R₂₈ each time taken is independently selectedfrom the group consisting of hydrogen and C₁-C₆ alkyl; R₄ is selectedfrom the group consisting of hydrogen, —C(O)R₁₀, —C(O)—(CH₂)_(q)—K and—S-G wherein R₁₀ is selected from the group consisting of hydrogen,C₁-C₄ alkyl, phenyl, and benzyl; q is 0, 1, or 2; K is selected from thegroup consisting of

wherein V is selected from the group consisting of a bond, —CH₂—, —O—,—S(O)_(r)—, —NR₂₁—, and —NC(O)R₂₂; wherein r is 0, 1, or 2; R₂₁ isselected from the group consisting of hydrogen, C₁-C₄ alkyl, and benzyl;R₂₂ is selected from the group consisting of hydrogen, —CF₃, C₁-C₁₀alkyl, phenyl, and benzyl; R₁₁ each time taken is independently selectedfrom the group consisting of hydrogen, C₁-C₄ alkyl, and benzyl; G isselected from the group consisting of

wherein w is an integer from 1 to 3; R₁₂ is selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, —CH₂CH₂S(O)_(u)CH₃, and benzyl;wherein u is 0, 1, or 2; R₁₃ is selected from the group consisting ofhydrogen, hydroxy, amino, C₁-C₆ alkyl, N-methylamino, N,N-dimethylamino,—CO₂R₁₇, and —OC(O)R₁₈; wherein R₁₇ is hydrogen, —CH₂O—C(O)C(CH₃)₃,C₁-C₄ alkyl, benzyl, or diphenylmethyl; R₁₈ is hydrogen, C₁-C₆ alkyl orphenyl; R₁₄ is 1 or 2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen; V₁ isselected from the group consisting of —O—, —S—, and —NH—; V₂ is selectedfrom the group consisting of —N— and —CH—; V₃ is selected from the groupconsisting of a bond and —C(O)—; V₄ is selected from the groupconsisting of —O—, —S—, —NR₁₉—, and —NC(O)R₂₀—; wherein R₁₉ is hydrogen,C₁-C₄ alkyl, or benzyl; R₂₀ is hydrogen, —CF₃, C₁-C₁₀ alkyl, or benzyl;R₁₅ is selected from the group consisting of hydrogen, C₁-C₆ alkyl andbenzyl; R₁₆ is selected from the group consisting of hydrogen and C₁-C₆alkyl; provided that when p is an integer from 1-10 and Ar₃ is

where R₂₃ is hydrogen or C₁-C₄ alkyl, that all are not concurrentlypresent; or a stereoisomer, pharmaceutically acceptable salt, or hydratethereof.
 14. A pharmaceutical composition comprising an effective matrixmetalloproteinases inhibitory amount of a compound of claim 13 inadmixture of otherwise in association one or more pharmaceuticallyacceptable carriers or excipients.
 15. A compound of the formula

wherein Aa is —NRR′; wherein R and R′ are independently selected fromthe group consisting of hydrogen and C₁-C₆ alkyl or R and R′ takentogether with the nitrogen atom to which they are attached form aN-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; R₁ isselected from the group consisting of hydrogen, C₁-C₆ alkyl,—(CH₂)_(a)—CO₂R₅, —(CH₂)_(a)C(O)NH₂, (CH₂)₄NH₂, —(CH₂)₃NH—C(NH)NH₂,(CH₂)₂—S(O)_(b)—CH₃, —CH₂OH, —CH(OH)CH₃, —CH₂—SH, —(CH₂)_(d)—Ar₁, and—CH₂—Ar₂; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0to 4; R₅ is selected from the group consisting of hydrogen, C₁-C₄ alkyl,and benzyl; Ar₁ is a radical selected from the group consisting of

wherein R₆ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy; R₇ is selected from the group consisting of hydrogen, halogen,C₁-C₄ alkyl, and C₁-C₄ alkoxy; Ar₂ is a radical selected from the groupconsisting of

R₂ is from 1 to 2 substituents independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁-C₄ alkyl, and C₁-C₄ alkoxy;R₃ is selected from the group consisting of —(CH₂)_(m)—W, —(CH₂)_(p)Ar₃,—(CH₂)_(k)—CO₂R₉, —(CH₂)_(m)—NR_(8′)SO₂Y₁, and (CH₂)_(m)-Z-Q wherein mis an integer from 2 to 8; p is an integer from 0-10; k is an integerfrom 1 to 9; W is phthalimido; Ar₃ is selected from the group consistingof

wherein R₂₃ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy;R_(8′) is hydrogen or C₁-C₆ alkyl; R₉ is hydrogen or C₁-C₆ alkyl; Y₁ isselected from the group consisting of hydrogen, —(CH₂)_(n)—Ar₄, and—N(R₂₄)₂ wherein j is 0 or 1; R₂₄ each time selected is independentlyhydrogen or C₁-C₆ alkyl or are taken together with the nitrogen to whichthey are attached to form N-morpholino, N-piperidino, N-pyrrolidino, orN-isoindolyl; Ar₄ is

wherein R₂₅ is from 1 to 3 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy; Zis selected from the group consisting of —O—, —NR₈—, —C(O)NR₈—,—NR₈C(O)—, —NR₈C(O)NH—, —NR₈C(O)O—, and —OC(O)NH—; wherein R₈ ishydrogen or C₁-C₆ alkyl; Q is selected from the group consisting ofhydrogen, —(CH₂)_(n)—Y₂, and —(CH₂)_(x)Y₃; wherein n is an integer from0 to 4; Y₂ is selected from the group consisting of hydrogen,—(CH₂)_(h)—Ar₅ and —(CH₂)_(t)—C(O)OR₂₇ wherein Ar₅ is selected from thegroup consisting of

 wherein  R₂₆ is from 1 to 3 substituents independently selected fromthe group consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄alkoxy;h is an integer from 0 to 6; t is an integer from 1 to 6; R₂₇ ishydrogen or C₁-C₆ alkyl; x is an integer from 2 to 4; Y₃ is selectedfrom the group consisting of —N(R₂₈)₂, N-morpholino, N-piperidino,N-pyrrolidino, and N-isoindolyl; wherein R₂₈ each time taken isindependently selected from the group consisting of hydrogen and C₁-C₆alkyl; R₁ is selected from the group consisting of hydrogen, —C(O)R₁₀,—C(O)—(CH₂)_(q)—K and —S-G wherein R₁₀ is selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, phenyl, and benzyl; q is 0, 1, or2; K is selected from the group consisting of

wherein V is selected from the group consisting of a bond, —CH₂—, —O—,—S(O)r, NR₂₁—, and —NC(O)R₂₂; wherein r is 0, 1, or 2; R₂₁ is selectedfrom the group consisting of hydrogen, C₁-C₄ alkyl, and benzyl; R₂₂ isselected from the group consisting of hydrogen, —CF₃, C₁-C₁₀ alkyl,phenyl, and benzyl; R₁₁ each time taken is independently selected fromthe group consisting of hydrogen, C₁-C₄ alkyl, and benzyl; G is selectedfrom the group consisting of

wherein w is an integer from 1 to 3; R₁₂ is selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, —CH₂CH₂S(O)_(u)CH₃, and benzyl;wherein u is 0, 1, or 2; R₁₃ is selected from the group consisting ofhydrogen, hydroxy, amino, C₁-C₆ alkyl, N-methylamino, N,N-dimethylamino,—CO₂R₁₇, and —OC(O)R₁₈; wherein R₁₇ is hydrogen, —CH₂O—C(O)C(CH₃)₃,C₁-C₄ alkyl, benzyl, or diphenylmethyl; R₁₈ is hydrogen, C₁-C₆ alkyl orphenyl; R₁₄ is 1 or 2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen; V₁ isselected from the group consisting of —O—, —S—, and —NH—; V₂ is selectedfrom the group consisting of —N— and —CH—; V₃ is selected from the groupconsisting of a bond and —C(O)—; V₄ is selected from the groupconsisting of —O—, —S—, —NR₁₉—, and —NC(O)R₂₀—; wherein R₁₉ is hydrogen,C₁-C₄ alkyl, or benzyl; R₂₀ is hydrogen, —CF₃, C₁-C₁₀ alkyl, or benzyl;R₁₅ is selected from the group consisting of hydrogen, C₁-C₆ alkyl andbenzyl; R₁₆ is selected from the group consisting of hydrogen and C₁-C₄alkyl; provided that p is not an integer from 1-10; or a stereoisomer,pharmaceutically acceptable salt, or hydrate thereof.
 16. Apharmaceutical composition comprising an effective matrixmetalloproteinases inhibitory amount of a compound of claim 15 inadmixture of otherwise in association with one or more pharmaceuticallyacceptable carriers or excipients.
 17. A compound of the formula

wherein Aa is —NRR′; wherein R and R′ are independently selected fromthe group consisting of hydrogen and, C₁-C₆ alkyl or R and R′ takentogether with the nitrogen atom to which they are attached form aN-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; R₁ isselected from the group consisting of hydrogen, C₁-C₆ alkyl,—(CH₂)_(a)—CO₂R₅, (CH₂)_(a)C(O)NH₂, (CH₂)₄NH₂, (CH₂)₃NHC(NH)NH₂,(CH₂)₂S(O)_(b)CH₃, CH₂OH, —CH(OH)CH₃, —CH₂—SH, —(CH₂)_(d)—Ar₁, and—CH₂—Ar₂; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0to 4; R₅ is selected from the group consisting of hydrogen, C₁-C₄ alkyl,and benzyl; Ar₁ is a radical selected from the group consisting of

wherein R₆ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy; R₇ is selected from the group consisting of hydrogen, halogen,C₁-C₄ alkyl, and C₁-C₄ alkoxy; Ar₂ is a radical selected from the groupconsisting of

R₂ is from 1 to 2 substituents independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁-C₄ alkyl, and C₁-C₄ alkoxy;R₃ is selected from the group consisting of —(CH₂)_(m)—W,—(CH₂)_(p)—Ar₃, —(CH₂)_(k)—CO₂R₉, —(CH₂)_(m)—NR_(8′)SO₂—Y₁, and(CH₂)_(m)-Z-Q wherein m is an integer from 2 to 8; p is an integer from0-10; k is an integer from 1 to 9; W is phthalimido; Ar₃ is selectedfrom the group consisting of

wherein R₂₃ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy; R₈is hydrogen or C₁-C₆ alkyl; R₉ is hydrogen or C₁-C₆ alkyl; Y₁ isselected from the group consisting of hydrogen, —(CH₂)_(t)—Ar₄, and—N(R₂₄)₂ wherein j is 0 or 1; R₂₄ each time selected is independentlyhydrogen or C₁-C₆ alkyl or are taken together with the nitrogen to whichthey are attached to form N-morpholino, N-piperidino, N-pyrrolidino, orN-isoindolyl; Ar₄ is

wherein R₂₅ is from 1 to 3 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy; Zis selected from the group consisting of —O—, —NR₈—, —C(O)NR₈—,—NR₈C(O)—, —NR₈C(O)NH—, —NR₈C(O)O—, and —OC(O)NH—; wherein R₈ ishydrogen or C₁-C₆ alkyl; Q is selected from the group consisting ofhydrogen, —(CH₂)_(n)—Y₂, and —(CH₂)_(x)Y₃; wherein n is an integer from0 to 4; Y₂ is selected from the group consisting of hydrogen,—(CH₂)_(h)—Ar₅ and —(CH₂)_(t)—C(O)OR₂₇ wherein Ar₅ is selected from thegroup consisting of

 wherein  R₂₆ is from 1 to 3 substituents independently selected fromthe group consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄alkoxy;h is an integer from 0 to 6; t is an integer from 1 to 6; R₂₇ ishydrogen or C₁-C₆ alkyl; x is an integer from 2 to 4; Y₃ is selectedfrom the group consisting of —N(R₂₈)₂, N-morpholino, N-piperidino,N-pyrrolidino, and N-isoindolyl; wherein R₂₈ each time taken isindependently selected from the group consisting of hydrogen and C₁-C₆alkyl; R₄ is selected from the group consisting of hydrogen, —C(O)R₁₀,—C(O)—(CH₂)_(q)—K and —S-G wherein R₁₀ is selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, phenyl, and benzyl; q is 0, 1, or2; K is selected from the group consisting of

wherein V is selected from the group consisting of a bond, —CH₂—, —O—,—S(O)_(r)—, NR₂₁ —, and —NC(O)R₂₂; wherein r is 0, 1, or 2; R₂₁ isselected from the group consisting of hydrogen, C₁-C₄ alkyl, and benzyl;R₂₂ is selected from the group consisting of hydrogen, —CF₃, C₁-C₁₀alkyl, phenyl, and benzyl; R₁₁ each time taken is independently selectedfrom the group consisting of hydrogen, C₁-C₄ alkyl, and benzyl; G isselected from the group consisting of

wherein w is an integer from 1 to 3; R₁₂ is selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, —CH₂CH₂S(O)_(u)CH₃, and benzyl;wherein u is 0, 1, or 2; R₁₃ is selected from the group consisting ofhydrogen, hydroxy, amino, C₁-C₆ alkyl, N-methylamino, N,N-dimethylamino,—CO₂R₁₇, and —OC(O)R₁₈; wherein R₁₇ is hydrogen, —CH₂O—C(O)C(CH₃)₃,C₁-C₄ alkyl, benzyl, or diphenylmethyl; R₁₈ is hydrogen, C₁-C₆ alkyl orphenyl; R₁₄ is 1 or 2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen; V₁ isselected from the group consisting of —O—, —S—, and —NH—; V₂ is selectedfrom the group consisting of —N— and —CH—; V₃ is selected from the groupconsisting of a bond and —C(O)—; V₄ is selected from the groupconsisting of —O—, —S—, —NR₁₉—, and —NC(O)R₂₀—; wherein R₁₉ is hydrogen,C₁-C₄ alkyl, or benzyl; R₂₀ is hydrogen, —CE₃, C₁-C₁₀ alkyl, or benzyl;R₁₅ is selected from the group consisting of hydrogen, C₁-C₆ alkyl andbenzyl; R₁₆ is selected from the group consisting of hydrogen and C₁-C₄alkyl; provided that Ar₃ is not

or a stereoisomer, pharmaceutically acceptable salt, or hydrate thereof.18. A pharmaceutical composition comprising a effective matrixmetalloproteinases inhibitory amount of a compound of claim 17 inadmixture of otherwise in association with one or more pharmaceuticallyacceptable carriers or excipients.
 19. A compound of the formula

wherein Aa is —NRR′; wherein R and R′ are independently selected fromthe group consisting of hydrogen and C₁-C₆ alkyl or R and R′ takentogether with the nitrogen atom to which they are attached form aN-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; R₁ isselected from the group consisting of hydrogen, C₁-C₆ alkyl,—(CH₂)_(a)—CO₂R₅, —(CH₂)_(a)C(O)NH₂, (CH₂)₄NH₂, (CH₂)₃—NH—C(NH)NH₂,—(CH₂)₂S(O)_(b)CH₃, CH₂OH, —CH(OH)CH₃, —CH₂—SH, —(CH₂)_(d)—Ar₁, and—CH₂—Ar₂; wherein a is 1 or 2; b is 0, 1, or 2; d is an integer from 0to 4; R₅ is selected from the group consisting of hydrogen, C₁-C₄ alkyl,and benzyl; Ar₁ is a radical selected from the group consisting of

wherein R₆ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, hydroxy, and C₁-C₄alkoxy; R₇ is selected from the group consisting of hydrogen, halogen,C₁-C₄ alkyl, and C₁-C₄ alkoxy; Ar₂ is a radical selected from the groupconsisting of

R₂ is from 1 to 2 substituents independently selected from the groupconsisting of hydrogen, halogen, hydroxy, C₁-C₄ alkyl, and C₁-C₄ alkoxy;R₃ is selected from the group consisting of —(CH₂)_(m)—W,—(CH₂)_(p)—Ar₃, —(CH₂)_(k)—CO₂R₉, —(CH₂)_(m)—NR_(8′)SO₂Y₁, and(CH₂)_(m)-Z-Q wherein m is an integer from 2 to 8; p is an integer from0-10; k is an integer from 1 to 9; W is phthalimido; Ar₃ is selectedfrom the group consisting of

wherein R₂₃ is from 1 to 2 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy; R₈is hydrogen or C₁-C₆ alkyl; R₉ is hydrogen or C₁-C₆ alkyl; Y₁ isselected from the group consisting of hydrogen, —(CH₂)₁—Ar₄, and—N(R₂₄)₂ wherein j is 0 or 1; R₂₄ each time selected is independentlyhydrogen or C₁-C₆ alkyl or are taken together with the nitrogen to whichthey are attached to form N-morpholino, N-piperidino, N-pyrrolidino, orN-isoindolyl; Ar₄ is

wherein R₂₅ is from 1 to 3 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy; Zis selected from the group consisting of —O—, —NR₈—, —C(O)NR₉—,—NR₈C(O)—, —NR₈C(O)NH—, —NR₈C(O)O—, and —OC(O)NH—; wherein R₈ ishydrogen or C₁-C₆ alkyl; Q is selected from the group consisting ofhydrogen, —(CH₂)_(n)—Y₂, and —(CH₂)_(x)Y₃; wherein n is an integer from0 to 4; Y₂ is selected from the group consisting of hydrogen,—(CH₂)_(h)—Ar₅ and —(CH₂)_(t)—C(O)OR₂₇ wherein Ar₅ is selected from thegroup consisting of

wherein R₂₆ is from 1 to 3 substituents independently selected from thegroup consisting of hydrogen, halogen, C₁-C₄ alkyl, and C₁-C₄alkoxy; his an integer from 0 to 6; t is an integer from 1 to 6; R₂₇ is hydrogenor C₁-C₆ alkyl; x is an integer from 2 to 4; Y₃ is selected from thegroup consisting of —N(R₂₈)₂, N-morpholino, N-piperidino, N-pyrrolidino,and N-isoindolyl; wherein R₂₈ each time taken is independently selectedfrom the group consisting of hydrogen and C₁-C₆ alkyl; R₄ is selectedfrom the group consisting of hydrogen, —C(O)R₁₀, —C(O)—(CH₂)_(q)—K and—S-G wherein R₁₀ is selected from the group consisting of hydrogen,C₁-C₄ alkyl, phenyl, and benzyl; q is 0, 1, or 2; K is selected from thegroup consisting of

wherein V is selected from the group consisting of a bond, —CH₂—, —O—,—S(O)_(r)—, NR₂₁—, and —NC(O)R₂₂; wherein r is 0, 1, or 2; R₂₁ isselected from the group consisting of hydrogen, C₁-C₄ alkyl, and benzyl;R₂₂ is selected from the group consisting of hydrogen, —CF₃, C₁-C₁₀alkyl, phenyl, and benzyl; R₁₁ each time taken is independently selectedfrom the group consisting of hydrogen, C₁-C₄ alkyl, and benzyl; G isselected from the group consisting of

wherein w is an integer from 1 to 3; R₁₂ is selected from the groupconsisting of hydrogen, C₁-C₆ alkyl, —CH₂CH₂S(O)_(u)CH₃, and benzyl;wherein u is 0, 1, or 2; R₁₃ is selected from the group consisting ofhydrogen, hydroxy, amino, C₁-C₆ alkyl, N-methylamino, N,N-dimethylamino,—CO₂R₁₇, and —OC(O)R₁₈; wherein R₁₇ is hydrogen, —CH₂O—C(O)C(CH₃)₃,C₁-C₄ alkyl, benzyl, or diphenylmethyl; R₁₈ is hydrogen, C₁-C₆ alkyl orphenyl; R₁₄ is 1 or 2 substituents independently selected from the groupconsisting of hydrogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, or halogen; V₁ isselected from the group consisting of —O—, —S—, and —NH—; V₂ is selectedfrom the group consisting of —N— and —CH—; V₃ is selected from the groupconsisting of a bond and —C(O)—; V₄ is selected from the groupconsisting of —O—, —S—, —NR₁₉—, and —NC(O)R₂₀—; wherein R₁₉ is hydrogen,C₁-C₄ alkyl, or benzyl; R₂₀ is hydrogen, —CF₃, C₁-C₁₀ alkyl, or benzyl;R₁₅ is selected from the group consisting of hydrogen, C₁-C₆ alkyl andbenzyl; R₁₆ is selected from the group consisting of hydrogen and C₁-C₄alkyl; provided that R₂₃ is not hydrogen or C₁-C₄ alkyl; or astereoisomer, pharmaceutically acceptable salt, or hydrate thereof. 20.A pharmaceutical composition comprising an effective matrixmetalloproteinases inhibitory amount of a compound of claim 19 inadmixture of otherwise in association with one or more pharmaceuticallyacceptable carriers or excipients.